Pharmaceutical formulations containing an SGLT2 inhibitor

ABSTRACT

Pharmaceutical formulations are provided which are in the form of capsules or tablets for oral use and which include a medicament dapagliflozin or its propylene glycol hydrate 
                         
and a pharmaceutical acceptable carrier therefor, which formulation is designed for immediate release.

This application is a divisional of U.S. patent application Ser. No.12/053,442, the priority of which under 35 U.S.C. §120 is herebyclaimed. U.S. patent application Ser. No. 12/053,442 claims priority toU.S. Provisional Patent Application Ser. No. 60/896,286, filed on Mar.22, 2007, the priority of which under 35 U.S.C. §119 is hereby claimed.

FIELD OF THE INVENTION

The present invention provides an immediate release pharmaceuticalformulation which includes a tablet or capsule formulation containingthe sodium dependent glucose transporter (SGLT2) inhibitor dapagliflozinor its propylene glycol hydrate.

BACKGROUND OF THE INVENTION

At least 171 million people worldwide suffer from type II diabetes(NIDDM), which is characterized by hyperglycemia due to excessivehepatic glucose production and peripheral insulin resistance.Hyperglycemia is considered to be the major risk factor for thedevelopment of diabetic complications, and is likely to contributedirectly to the impairment of insulin secretion seen in advanced NIDDM.Thus, consistent control of plasma glucose levels in NIDDM patients canoffset the development of diabetic complications and beta cell failureseen in advanced disease. Plasma glucose is normally filtered in thekidney in the glomerulus and actively reabsorbed in the proximal tubule.SGLT2 appears to be the major transporter responsible for the reuptakeof glucose at this site. A selective inhibitor of the sodium-dependentglucose transporter SGLT2 in the kidney is expected to normalize plasmaglucose levels by enhancing the excretion of glucose in the urine,thereby improving insulin sensitivity, and delaying the development ofdiabetic complications.

The compound of the structure (I)

or pharmaceutically acceptable salts or solvates thereof (hereinafterdapagliflozin), an orally active SGLT2 inhibitor is disclosed in U.S.Pat. No. 6,515,117 (the disclosure of which is incorporated herein byreference in its entirety).

U.S. application Ser. No. 11/765,481 filed Jun. 28, 2007, published asUS 2008-0004336 A1 discloses dapagliflozin in the form of its(S)-propylene glycol ((S)-PG) hydrate and its (R)-propylene glycol((R)-PG) hydrate. The (S)-propylene glycol hydrate is referred to asform SC-3 and has the structure shown as (Ia).

The (R)-propylene glycol hydrate is referred to as form SD-3 and has thestructure shown as (Ib).

Methods for preparing the (S)-PG hydrate and the (R)-PG hydrate ofdapagliflozin are provided in U.S. application Ser. No. 11/765,481 filedJun. 28, 2007, published as US 2008-0004336 A1 (the disclosure of whichis incorporated herein by reference in its entirety).

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, pharmaceutical formulationsare provided which can be in the form of a capsule formulation or atablet formulation, for oral use, designed for immediate release, andinclude as the medicament dapagliflozin which has the structure (I)

or a pharmaceutically acceptable salt, solvate, mixed solvate, orcomplex thereof (which is disclosed in U.S. Pat. No. 6,515,117 hereinincorporated by reference in its entirety) and a pharmaceuticallyacceptable carrier thereof.

In one embodiment, the dapagliflozin is in the form of its (S)-propyleneglycol ((S)-PG) hydrate (SC-3) which is shown as Compound (Ia)

the preparation for which is disclosed in U.S. application Ser. No.11/765,481, filed Jun. 28, 2007, U.S. Publication No. 2008-0004336 A1,and Provisional Application No. 60/817,118, filed Jun. 28, 2006, thedisclosures of both of which are incorporated herein by reference intheir entireties.

In another embodiment, the dapagliflozin is in the form of its(R)-propylene glycol ((R)-PG) hydrate (SD-3), which is shown as Compound(Ib)

the preparation for which is disclosed in U.S. application Ser. No.11/765,481, filed Jun. 28, 2007, U.S. Publication No. 2008-0004336 A1,and Provisional Application No. 60/817,118, filed Jun. 28, 2006, thedisclosures of both of which are incorporated herein by reference intheir entireties.

In one embodiment of the invention, the immediate release pharmaceuticalformulation of the invention is in the form of a stock granulation(e.g., granules, beads, and/or beadlets), for loading in capsules orforming into tablets, comprising

-   -   a) dapagliflozin or dapagliflozin propylene glycol hydrate;    -   b) one or more bulking agents;    -   c) optionally one or more binders;    -   d) optionally one or more disintegrants;    -   e) optionally one or more glidants and/or anti-adherents; and    -   f) optionally one or more lubricants.

In one embodiment, the stock granulation comprises dapagliflozin and oneor more bulking agents. In another embodiment, the stock granulationcomprises dapagliflozin propylene glycol hydrate and one or more bulkingagents. Suitable bulking agents include, for example, microcrystallinecellulose and/or lactose, as well as others provided herein and known inthe art. In other embodiments, the stock granulation optionallycomprises one or more of the following compounds: (1) one or morebinders; (2) one or more disintegrants; (3) one or more glidants and/oranti-adherents; and (4) one or more lubricants. Suitable bindersinclude, for example, pregelatinized starch, as well as others providedherein and known in the art. Suitable disintegrants include, forexample, sodium starch glycolate, crospovidone, and croscamellosesodium, as well as others provided herein and known in the art. Suitableglidants and/or anti-adherents include, for example, silicon dioxide andtalc, as well as others provided herein and known in the art. Suitablelubricants include, for example, magnesium stearate, as well as othersprovided herein and known in the art.

The stock granulation of the invention as described above, and capsulesand tablets containing same, is prepared by mixing togetherdapagliflozin or dapagliflozin propylene glycol and one or more bulkingagents, in any desired order, to form the stock granulation; and fillingthe capsules with or forming tablets from desired quantities of thestock granulation. In other embodiments, the stock granulation of theinvention is prepared by mixing together dapagliflozin or dapagliflozinpropylene glycol hydrate and one or more bulking agents; and optionallyone or more of the following compounds: binder(s); disintegrant(s);glidant(s) and/or anti-adherent(s); and lubricant(s) in any desiredorder, to form the stock granulation and filling the capsules with orforming tablets from desired quantities of stock granulation.

The tablets of the invention as described above are prepared bycompressing the stock granulation into tablet form. In one embodiment,the tablets of the invention are prepared by compressing the stockgranulation having one or more binder(s). In another embodiment, thetablets of the invention are prepared by compressing the stockgranulation containing one or more anti-adherent(s) and/or glidant(s).In other embodiments, the tablets of the invention are prepared bycompressing the stock granulation comprising one or more of thefollowing compounds: (1) one or more binders; (2) one or moredisintegrants; (3) one or more glidants and/or anti-adherents; and (4)one or more lubricants.

Optionally, the tablets and/or capsules of the invention can include anouter protective coating which comprises a coating polymer, such as, forexample, polyvinyl alcohol (PVA), hydroxypropyl methyl cellulose, andhydroxypropyl cellulose, and/or a plasticizer(s) and optionalcolorant(s). Other optional components of the outer protective coatinginclude anti-adherent(s) and/or glidant(s) and opacifying agent(s).

The pharmaceutical dapagliflozin and dapagliflozin propylene glycolhydrate formulations of the invention including the stock granulation,capsules containing same, and tablets of the invention are useful in thetreatment of mammals, such as humans, dogs, and cats, for diseases ordisorders associated with SGLT2 activity. Thus, the invention providespharmaceutical dapagliflozin formulations and dapagliflozin propyleneglycol hydrate formulations for use in the treatment of diseases ordisorders associated with SGLT2 activity, for example, Type I and TypeII diabetes; impaired glucose tolerance; insulin resistance; anddiabetic complications, such as nephropathy, retinopathy, neuropathy andcataracts; hyperglycemia; hyperinsulinemia; hypercholesterolemia;dyslipidemia; elevated blood levels of free fatty acids or glycerol;hyperlipidemia; hypertriglyceridemia; obesity; wound healing; tissueischemia; atherosclerosis; hypertension; and Syndrome X or MetabolicSyndrome.

In one embodiment, the invention provides the pharmaceutical formulationof the invention for use in the treatment of type II diabetes. Inanother embodiment, the invention provides the pharmaceuticalformulation of the invention for use in delaying the progression oronset of type II diabetes.

The invention further provides a method for treating or delaying theprogression or onset of diseases or disorders associated with SGLT2activity comprising administering to a mammalian species in need of suchtreatment a therapeutically effective amount of a pharmaceuticalformulation of the invention. In one embodiment, the invention providesa method for treating type II diabetes comprising administering to amammalian species in need of such treatment a therapeutically effectiveamount of a pharmaceutical formulation of the invention. In oneembodiment, the invention provides a method for delaying the progressionor onset of type II diabetes comprising administering to a mammalianspecies in need of such treatment a therapeutically effective amount ofa pharmaceutical formulation of the invention.

Other therapeutic agent(s) suitable for combination with theformulations of the present invention include, but are not limited to,known therapeutic agents useful in the treatment of the aforementioneddisorders associated with SGLT2 activity including: anti-diabeticagents; anti-hyperglycemic agents; hypolipidemic or lipid loweringagents; anti-obesity agents; anti-hypertensive agents and appetitesuppressants.

The invention further provides a method for treating or delaying theprogression or onset of diseases or disorders associated with SGLT2activity comprising administering to a mammalian species in need of suchtreatment a therapeutically effective amount of a pharmaceuticalformulation of the invention and one or more of the following: ananti-diabetic agent(s), anti-hyperglycemic agent(s); hypolipidemic orlipid lowering agent(s); anti-obesity agent(s); anti-hypertensiveagent(s) and appetite suppressant(s).

In one embodiment, the invention provides a method for treating type IIdiabetes comprising administering to a mammalian species in need of suchtreatment a therapeutically effective amount of a pharmaceuticalformulation of the invention and one or more anti-diabetic agent(s). Inone embodiment, the invention provides a method for delaying theprogression or onset of type II diabetes comprising administering to amammalian species in need of such treatment a therapeutically effectiveamount of a pharmaceutical formulation of the invention and one or moreanti-diabetic agent(s). In one embodiment, the invention provides amethod for treating or delaying the progression or onset of type IIdiabetes comprising administering to a mammalian species in need of suchtreatment a therapeutically effective amount of a pharmaceuticalformulation of the invention and one or more of the following: ananti-hyperglycemic agent(s); hypolipidemic or lipid lowering agent(s);anti-obesity agent(s); anti-hypertensive agent(s) and appetitesuppressant(s).

DETAILED DESCRIPTION OF THE INVENTION

The invention provides immediate release pharmaceutical formulations,which include, among others, tablet and capsule formulations, containingthe sodium dependent glucose transporter (SGLT2) inhibitor dapagliflozinor its propylene glycol hydrate.

As used herein, the term “dapagliflozin” is intended to mean thestructure shown as structure I or Compound I. The term “dapagliflozinpropylene glycol hydrate” is meant to refer to and encompass bothdapagliflozin (S)-propylene glycol hydrate (structure Ia or Compound Ia)and dapagliflozin (R)-propylene glycol hydrate (structure Ib or CompoundIb). As used herein, the terms “pharmaceutical formulation”,“pharmaceutical formulation of the invention”, and “formulation” aremeant to refer to formulations containing dapagliflozin as well asformulations containing dapagliflozin propylene glycol hydrate.Likewise, the term “medicament” is meant in the present application torefer to dapagliflozin and dapagliflozin propylene glycol hydrate.

As used herein, the terms “immediate release” and “immediate releasepharmaceutical formulation” are intended to mean that the pharmaceuticalformulations of the invention are not produced using excipients thatinterfere with absorption of the active pharmaceutical ingredient, forexample, dapagliflozin or dapagliflozin propylene glycol hydrate, whenadministered to a mammal or human.

The pharmaceutical formulation of the invention can be in the form of acapsule, tablet, bead, beadlet, granule or pill, all of the above beingcollectively referred to as pharmaceutical formulations, and containsmedicament, namely dapagliflozin or dapagliflozin propylene glycolhydrate. In one embodiment, the medicament is dapagliflozin. In oneembodiment, the medicament is dapagliflozin (S)-propylene glycolhydrate. In another embodiment, the medicament is dapagliflozin(R)-propylene glycol hydrate. In one embodiment of the invention, theimmediate release pharmaceutical formulation of the invention is in theform of a stock granulation (e.g., granules, beads, and/or beadlets),for loading in capsules or forming into tablets.

In one embodiment, the dapagliflozin or dapagliflozin propylene glycolhydrate is in an amount within the range of from about 0.1% to about 70%by weight of the stock granulation and preferably in an amount withinthe range of from about 0.1% to about 30% by weight of the stockgranulation.

The pharmaceutical formulation of the invention can includepharmaceutical excipients as described herein to aid in the formation ofa stock granulation suitable in the form of granules, beads, or beadletsfor capsule loading and for tablets of the invention. In one embodiment,the pharmaceutical formulation is in the form of a capsule or tabletcontaining a stock granulation comprising

-   -   a) dapagliflozin or dapagliflozin propylene glycol hydrate;    -   b) at least one bulking agent or filler;    -   c) optionally at least one binder;    -   d) optionally at least one disintegrant;    -   e) optionally at least one glidant and/or anti-adherent; and    -   f) optionally at least one lubricant.

In the described embodiments of the pharmaceutical formulations of theinvention, the amounts of medicament (dapagliflozin or dapagliflozinpropylene glycol hydrate) and each of the excipient(s) are expressed asa percentage weight of the total weight of the stock granulation, whichis equivalent in measurement to the percentage weight of the totalweight of the tablet or capsule fill.

In one embodiment, the dapagliflozin or dapagliflozin propylene glycolhydrate is in an amount within the range of from about 0.1% to about 70%by weight of the stock granulation. In another embodiment, thedapagliflozin or dapagliflozin propylene glycol hydrate is in an amountwithin the range of from about 0.1% to about 30% by weight of the stockgranulation.

In one embodiment, the bulking agent or filler is present in an amountwithin the range of from about 1% to about 95% by weight of the stockgranulation. In another embodiment, the bulking agent or filler ispresent in an amount within the range of from about 10% to about 85% byweight of the stock granulation.

In one embodiment, the binder, if present, is present in an amountwithin the range of from about 0% to about 20% by weight of the stockgranulation. In another embodiment, the binder, if present, is presentin an amount within the range of from about 1% to about 10% by weight ofthe stock granulation. In another embodiment, the binder, if present, ispresent in an amount within the range of from about 2% to about 4% byweight of the stock granulation.

In one embodiment, the disintegrant, if present, is present in an amountwithin the range of from about 0% to about 20% by weight of the stockgranulation. In another embodiment, the disintegrant, if present, ispresent in an amount within the range of from about 0.25% to about 10%by weight of the stock granulation.

In one embodiment, the glidant and/or anti-adherent, if present, ispresent in an amount within the range of from about 0% to about 20% byweight of the stock granulation. In another embodiment, the glidantand/or anti-adherent, if present, is present in an amount within therange of from about 1% to about 15% by weight of the stock granulation.

In one embodiment, the lubricant, if present, is present in an amountwithin the range of from about 0% to about 5% by weight of the stockgranulation. In another embodiment, the lubricant, if present, ispresent in an amount within the range of from about 0.1% to about 5% byweight of the stock granulation. In another embodiment, the lubricant,if present, is present in an amount within the range of from about 0.2%to about 2% by weight of the stock granulation.

In one embodiment, the pharmaceutical formulation is in the form of acapsule or tablet containing a stock granulation comprising

-   -   a) dapagliflozin or dapagliflozin propylene glycol hydrate;    -   b) at least one bulking agent or filler;    -   c) optionally at least one binder;    -   d) optionally at least one disintegrant;    -   e) optionally at least one glidant and/or anti-adherent; and    -   f) optionally at least one lubricant.        wherein    -   a) the dapagliflozin or dapagliflozin propylene glycol hydrate        is present in an amount within the range of from about 0.1% to        about 70% by weight;    -   b) the bulking agent or filler is present in an amount within        the range of from about 1% to about 95% by weight;    -   c) the binder, if present, is present in an amount within the        range of from about 0% to about 20% by weight;    -   d) the disintegrant, if present, is present in an amount within        the range of from about 0% to about 20% by weight;    -   e) the glidant and/or anti-adherent, if present, is present in        an amount within the range of from about 0% to about 20% by        weight; and    -   f) the lubricant, if present, is present in an amount within the        range of from about 0% to about 5% by weight, all of the above %        by weight being based on the weight of the stock granulation.

In one embodiment, the pharmaceutical formulation is in the form of acapsule or tablet containing a stock granulation comprising

-   -   a) dapagliflozin or dapagliflozin propylene glycol hydrate;    -   b) at least one bulking agent or filler;    -   c) optionally at least one binder;    -   d) optionally at least one disintegrant;    -   e) optionally at least one glidant and/or anti-adherent; and    -   f) optionally at least one lubricant.        wherein    -   a) the dapagliflozin or dapagliflozin propylene glycol hydrate        is present in an amount within the range of from about 0.1% to        about 30% by weight    -   b) the bulking agent or filler is present in an amount within        the range of from about 10% to about 85% by weight;    -   c) the binder, if present, is present in an amount within the        range of from about 1% to about 10% by weight;    -   d) the disintegrant, if present, is in an amount within the        range of from about 0.25% to about 10% by weight;    -   e) the glidant and/or anti-adherent, if present, is in an amount        within the range of from about 1% to about 15% by weight; and    -   f) the lubricant, if present, is in an amount within the range        of from about 0.2% to about 2% by weight, all of the above % by        weight being based on the weight of the stock granulation.

In one embodiment, the medicament in the pharmaceutical formulations has90% of the particles smaller than 200 micrometers. In anotherembodiment, the medicament has 90% of its particles smaller than 100micrometers. In another embodiment, the medicament has 90% of itsparticles smaller than 50 micrometers. Dapagliflozin or dapagliflozinpropylene glycol hydrate can be milled or micronized as needed to obtainthe above mentioned characteristics.

Examples of bulking agents or fillers suitable for use herein include,but are not limited to, cellulose derivatives, such as microcrystallinecellulose or wood cellulose, lactose, sucrose, starch, pregelatinizedstarch, dextrose, mannitol, fructose, xylitol, sorbitol, corn starch,modified corn starch, inorganic salts such as calcium carbonate, calciumphosphate, dicalcium phosphate, calcium sulfate, dextrin/dextrates,maltodextrin, compressible sugars, and other known bulking agents orfillers, and/or mixtures of two or more thereof. Several types ofmicrocrystalline cellulose are suitable for use in the formulationsdescribed herein, for example, microcrystalline cellulose selected fromthe group consisting of Avicel® types: PH101, PH102, PH103, PH105, PH112, PH113, PH200, PH301, and other types of microcrystalline cellulose,such as silicified microcrystalline cellulose. Several types of lactoseare suitable for use in the formulations described herein, for example,lactose selected from the group consisting of anhydrous lactose, lactosemonohydrate, lactose fast flo, directly compressible anhydrous lactose,and modified lactose monohydrate. In one embodiment of the invention,the bulking agent of the stock granulation is microcrystalline celluloseand/or lactose. Lactose is particularly useful for tablet formulation.

Examples of binders suitable for use herein include, but are not limitedto, hydroxypropyl cellulose, corn starch, pregelatinized starch,modified corn starch, polyvinyl pyrrolidone (PVP) (typical molecularweight ranging from about 5,000 to about 1,000,000, preferably about40,000 to 50,000), hydroxypropyl methylcellulose (HPMC), lactose, gumacacia, ethyl cellulose, cellulose acetate, as well as a wax binder suchas carnauba wax, paraffin, spermaceti, polyethylenes or microcrystallinewax, as well as other conventional binding agents and/or mixtures of twoor more thereof. In one embodiment of the invention, the binding agent,if present, of the stock granulation is pregelatinized starch.

Examples of disintegrants suitable for use herein include, but are notlimited to, croscarmellose sodium, crospovidone, starch, potato starch,pregelatinized starch, corn starch, sodium starch glycolate,microcrystalline cellulose, low substituted hydroxypropyl cellulose andother known disintegrants. Several specific types of disintegrant aresuitable for use in the formulations described herein. For example, anygrade of crospovidone can be used, including for example crospovidoneXL-10, and includes members selected from the group consisting ofKollidon Polyplasdone XL®, Kollidon CL-M®, Polyplasdone XL-10®, andPolyplasdone INF-10®. In one embodiment, the disintegrant, if present,of the stock granulation is sodium starch glycolate, croscarmellosesodium and/or crospovidone. In one embodiment, the disintegrant issodium starch glycolate. In another embodiment, the disintegrant iscroscarmellose sodium and/or crospovidone, which are particularly usefulfor tablet formulation. In one specific embodiment, the disintegrant iscrospovidone XL-10 with peroxide levels below 400 parts per million(ppm). These materials are also referred to as insoluble polyvidone,insoluble PVP, crosslinked PVP, and PVPP. The crospovidone can besubstituted with croscarmellose sodium, sodium starch glycolate, orpregelatinized starch (at, for example, a 5-10% concentration).

Examples of lubricants suitable for use herein include, but are notlimited to, magnesium stearate, zinc stearate, calcium stearate, talc,carnauba wax, stearic acid, palmitic acid, sodium stearyl fumaratesodium laurel sulfate, glyceryl palmitostearate, palmitic acid, myristicacid and hydrogenated vegetable oils and fats, as well as other knownlubricants, and/or mixtures of two or more thereof. In one embodiment,the lubricant, if present, of the stock granulation is magnesiumstearate.

Examples of glidants and/or anti-adherents suitable for use hereininclude but are not limited to, silicon dioxide (generally), colloidalsilicon dioxide, magnesium silicate, magnesium trisilicate, talc, andother forms of silicon dioxide, such as aggregated silicates andhydrated silica.

In one embodiment of the stock granulation, the bulking agent ismicrocrystalline cellulose and/or lactose monohydrate, the binder, ifpresent, is pregelatinized starch, the disintegrant, if present, issodium starch glycolate, croscarmellose sodium and/or crospovidone, thelubricant, if present, is magnesium stearate and the glidant and/oranti-adherent, if present, is silicon dioxide and/or talc.

In one embodiment, the tablet or capsule has a protective outer layer.The protective outer layer of the tablet or capsule, where present, caninclude from about 10% to about 95% of polymer based on the weight ofthe coating layer, and can be prepared employing conventionalprocedures. In one embodiment, the outer layer of the tablet or capsuleincludes from about 20% to about 90% of polymer based on the weight ofthe coating layer. The formulation can contain at least one coatinglayer polymer and a coating solvent, for example, water, which is usedfor processing and removed by drying. Suitable examples of polymer forthe coating layer include, but are not limited to, hydroxypropylmethylcellulose, polyvinyl alcohol (PVA), ethyl cellulose, methacrylicpolymers, hydroxypropyl cellulose, and starch. In one embodiment, thecoating layer polymer is PVA. In another embodiment, the coating layerpolymer is hydroxypropyl cellulose. Use of PVA allows for enhanced logodefinition, film adhesion, and facilitates faster coating of the drug,the latter of which can be important for dapagliflozin formulations dueto the temperature sensitivity of the compound.

The coating can also optionally include a plasticizer of from about 0%to about 30% by weight, based on the weight of the coating layer. In oneembodiment, the plasticizer is from about 15% to about 25% by weight ofthe coating layer. Suitable platicizers include, but are not limited to,triacetin, diethyl phthalate, tributyl sebacate, polyethylene glycol(PEG), glycerin, triacetin, and triaethyl citrate, for example. In oneembodiment, the platicizer is polyethylene glycol of molecular weight200 to 20,000. In another embodiment, the platicizer is polyethyleneglycol of molecular weight 400 to 4,000. In another embodiment, theplaticizer is polyethylene glycol of molecular weight 400.

In another embodiment, the coating can also optionally include ananti-adherent or glidant such as talc, fumed silica, or magnesiumstearate, for example. In another embodiment, the coating can alsooptionally include an opacifying agent, such as titanium dioxide, forexample. In yet another embodiment, the coating layer can alsooptionally include one or more colorants, for example, iron oxide basedcolorant(s). Examples of commercially available coating material includeOpadry® HP and Opadry® II white.

The pharmaceutical formulations disclosed herein can further compriseantioxidants and chelating agents. For example, the pharmaceuticalformulations can comprise butylated hydroxyanisole (BHA), butylatedhydroxytoluene (BHT), propyl gallate (PG), sodium metabisulfite,ascorbyl palmitate, potassium metabisulfite, disodium EDTA(ethylenediamine tetraacetic acid; also known as disodium edentate),EDTA, tartaric acid, citric acid, citric acid monohydrate, and sodiumsulfite. In one embodiment, the foregoing compounds are included in thepharmaceutical formulations in amounts in the range of about 0.01% toabout 5% w/w. In one specific embodiment, the pharmaceutical formulationincludes BHA, BHT, or PG used at a range of about 0.02% to about 1% anddisodium EDTA, citric acid, or citric acid monohydrate used at a rangeof about 2% to about 5%. In a preferred embodiment, the pharmaceuticalformulation includes BHA used at about 0.05% w/w.

The pharmaceutical formulations of the invention as described above areprepared by mixing together dapagliflozin or dapagliflozin propyleneglycol hydrate and one or more of the desired excipients describedherein in any desired order, to form the stock granulation; and fillingthe capsules with or forming tablets from desired quantities of thestock granulation. The stock granulation, capsules and tablets of theinvention can be prepared by a variety of processes and order ofaddition of excipients. The utility of these formulations is not limitedto a specific dosage form or manufacturing process. For example, stockformulation tablets can be manufactured by wet granulation, drygranulation, direct blending or any other pharmaceutically acceptableprocess described herein or otherwise known in the art.

The pharmaceutical formulations of the invention can be packaged in anypackaging that facilitates stability of the drug formulation. Forexample, sealed high density polyethylene (HDPE) bottles containingsilica gel desiccant or aluminum blister lined with PVC can be used. Useof such packaging helps to control unwanted oxidation of the product atroom temperature.

Examples of certain specific embodiments of tablet and capsuleformulations in accordance with the invention are set out below.

TABLE I Tablet and Capsule Formulations Possible Range Preferred Range %by weight % by weight of tablet of tablet or capsule fill or capsulefill Material Dapagliflozin or 0.1 to 70% 0.1 to 30% Dapagliflozinpropylene glycol hydrate Bulking Agent/binder 1 to 95% 10 to 85%Anhydrous Lactose 0 to 95% 20 to 75% Microcrystalline 0 to 95% 20 to 75%cellulose Pregelatinized starch 0 to 95% 10 to 75% Disintegrant 0 to 20%0.25 to 10% Croscarmellose sodium 0 to 20% 2 to 10% Crospovidone 0 to12% 4 to 10% Sodium Starch 0 to 20% 2 to 10% glycolate Lubricant 0.1 to5% 0.2 to 2% Magnesium Stearate 0.1 to 5% 0.2 to 2% Antiadherent/glidant 0 to 10% 1 to 10% Talc, silicon dioxide more preferably1 to 4% Outer Protective Coating Layer Coating polymer, and 0.5 to 50% 1to 5% optional plasticizer(s), glidant(s), anti-tacking agent(s), andcolorant(s)

TABLE II Granulation Composition (% w/w) for Tablets and CapsulesPossible Preferred Range range Ingredient % by weight % by weightDapagliflozin or Dapagliflozin 0.1-40  0.1-10  Propylene Glycol HydrateMicrocrystalline Cellulose q.s. q.s. Anhydrous Lactose  0-50 10-30Crospovidone  1-15  3-10 Silicon Dioxide 0-6 0.5-4  Magnesium Stearate0.0-4.0 0.5-2.0 q.s. refers to the quantity sufficient to make thegranulation composition 100% w/w.

A film coating for capsules or tablets of Table II comprises, forexample, polyvinyl alcohol (PVA), titanium dioxide, polyethylene glycol,talc, and colorant.

Tablets or capsules of various strengths (0.1-50 mg) can be preparedusing different weights of the stock granulations described herein.

The pharmaceutical formulation in the form of a tablet can be obtainedby a process comprising the steps of:

-   -   a) mixing the inactive ingredients with the medicament        (Dapagliflozin or Dapagliflozin propylene glycol hydrate) using        a combination of blending and milling processes;    -   b) formulating granules;    -   c) drying and/or screening the granules;    -   d) blending the granules; and    -   e) tabletting the blend obtained in (d) into tablets.

In one embodiment, step a) of the process employs impact milling and/orsizing equipment. In one embodiment, the granules in step b) of theprocess are formulated by dry granulation, wet granulation, or directcompression. In one embodiment, the granules are formulated by drygranulation. In one embodiment, the granules in step d) of the processare blended with a tableting aid or a lubricant and filler.

The pharmaceutical formulation in the form of a capsule can be obtainedby a process comprising the steps of:

-   -   a) mixing the inactive ingredients with the medicament using a        combination of blending and milling processes;    -   b) formulating granules;    -   c) drying and/or screening the granules; and    -   (d) loading the granules into capsules.

In one embodiment, step a) of the process employs impact milling and/orsizing equipment. In one embodiment, the granules in step b) of theprocess are formulated by dry granulation, wet granulation, or directcompression. In one embodiment, the granules are formulated by drygranulation.

The dapagliflozin propylene glycol hydrate ((S) form and (R) form) canbe prepared, for example, by a process as described in U.S. applicationSer. No. 11/765,481, filed Jun. 28, 2007, U.S. Publication No.2008-0004336 A1, and provisional application No. 60/817,118 filed Jun.28, 2006.

For example, dapagliflozin (S)-propylene glycol hydrate (Compound Ia)can be prepared by the following steps: providing a compound A (preparedas described in U.S. application Ser. No. 10/745,075 filed Dec. 23,2003, Examples 17 to 20), of the structure (A);

treating compound A with an alcohol solvent, such as methanol orethanol, and aqueous base, such as sodium hydroxide, and water, ifnecessary, under an inert atmosphere, and elevated temperature, ifnecessary; adding an acid, such as hydrochloric acid to neutralize thereaction mixture, to form compound I of the structure;

treating the reaction mixture containing compound I with an organicsolvent, such as methyl t-butyl ether, an alkyl acetate, such as ethylacetate, methyl acetate, isopropyl acetate, or butyl acetate, and(S)-propylene glycol; optionally adding seeds of (S)-propylene glycolcompound Ia (SC-3) to the mixture, to form dapagliflozin (S)-propyleneglycol compound Ia (SC-3 form).

In another example, dapagliflozin propylene glycol hydrate can beprepared in a process comprising the step of reducing a compound of thestructure (B)

to remove the methoxy group; treating compound B with a reducing agent,such as triethylsilyl hydride and an activating group which is a Lewisacid, such as BF₃.Et₂O, and an organic solvent, such as CH₃CN, andwater; separating out the compound of the structure (I);

and treating compound I with (S)-propylene glycol in the presence of asolvent, such as t-butylmethyl ether, and optionally with seeds ofcompound Ia (dapagliflozin (S)-propylene glycol), to form a crystalslurry of compound Ia (dapagliflozin (S)-propylene glycol) andseparating out compound Ia (dapagliflozin (S)-propylene glycol).

The above process of the invention is a one-pot operation whichminimizes the production of intermediates, resulting in improved yieldand priority of the final crystalline compound Iadapagliflozin(S)-propylene glycol.

In carrying out the formation of compound Ia, the (S)-propylene glycolis employed in a molar ratio to compound I with the range of from about0.9:1 to about 1.5:1. In one embodiment, the (S)-propylene glycol isemployed in a molar ratio to compound I with the range of from about0.98:1 to about 1.2:1.

Dapagliflozin (R)-propylene glycol hydrate (Compound Ib) can be preparedby the following steps: providing a compound A (prepared as described inU.S. application Ser. No. 10/745,075 filed Dec. 23, 2003, Examples 17 to20), of the structure (A);

treating compound A with an alcohol solvent, such as methanol orethanol, and aqueous base, such as sodium hydroxide, and water, ifnecessary, under an inert atmosphere, and elevated temperature, ifnecessary; adding an acid, such as hydrochloric acid to neutralize thereaction mixture, to form compound I of the structure;

treating the reaction mixture containing compound I with an organicsolvent, such as methyl t-butyl ether, an alkyl acetate, such as ethylacetate, methyl acetate, isopropyl acetate, or butyl acetate, and(R)-propylene glycol; optionally adding seeds of (R)-propylene glycolCompound Ib (SD-3) to the mixture, to form dapagliflozin (R)-propyleneglycol Compound Ib (SD-3 form).

The activity of dapagliflozin or dapagliflozin propylene glycol hydratecan be determined using, for example, the assay system described belowor any appropriate assay system known in the art.

The mRNA sequence for human SGLT2 (GenBank #M95549) is cloned byreverse-transcription and amplification from human kidney mRNA, usingstandard molecular biology techniques. The cDNA sequence is stablytransfected into CHO cells, and clones are assayed for SGLT2 activityessentially as described in Ryan et al., “HK-2: an immortalized proximaltubule epithelial cell line from normal adult human kidney”, KidneyInternational, 45:48-57 (1994). Evaluation of inhibition of SGLT2activity in a clonally selected cell line is performed essentially asdescribed in Ryan et al. (1994), with the following modifications. Cellsare grown in 96-well plates for 2-4 days to 75,000 or 30,000 cells perwell in F-12 nutrient mixture (Ham's F-12), 10% fetal bovine serum, 300ug/ml Geneticin and penicillin-streptomycin. At confluence, the cellsare washed twice with 10 mM Hepes/Tris, pH 7.4, 137 mMN-methyl-D-glucamine, 5.4 mM KCl, 2.8 mM CaCl₂, 1.2 mM MgSO₄. Cells arethen incubated with 10 μM [¹⁴C]AMG, and 10 μM inhibitor (finalDMSO=0.5%) in 10 mM Hepes/Tris, pH 7.4, 137 mM NaCl, 5.4 mM KCl, 2.8 mMCaCl₂, 1.2 mM MgSO₄ at 37° C. for 1.5 hours. Uptake assays are quenchedwith ice cold 1×PBS containing 0.5 mM phlorizin, and cells are thenlysed with 0.1% NaOH. After addition of MicroScint scintillation fluid,the cells are allowed to shake for 1 hour, and then [¹⁴C]AMG (glucoseanalog α-methyl-D-glucopyranoside) is quantitated on a TopCountscintillation counter. Controls are performed with and without NaCl. Fordetermination of EC₅₀ values, 10 inhibitor concentrations(dapagliflozin) are used over 2 log intervals in the appropriateresponse range, and triplicate plates are averaged across plates.

The pharmaceutical formulations of the present invention containingdapagliflozin or dapagliflozin propylene glycol hydrate possess activityas an inhibitor of the sodium dependent glucose transporters found inthe intestine and kidney of mammals, is a selective inhibitor of renalSGLT2 activity, and therefore can be used in the treatment of diseasesor disorders associated with SGLT2 activity.

Accordingly, the pharmaceutical dapagliflozin and dapagliflozinpropylene glycol hydrate formulations of the present invention can beadministered to mammals, preferably humans, for the treatment of avariety of conditions and disorders associated with SGLT2 activityincluding, but not limited to, treating or delaying the progression oronset of diabetes (including Type I and Type II diabetes, impairedglucose tolerance, insulin resistance, and diabetic complications, suchas nephropathy, retinopathy, neuropathy and cataracts), hyperglycemia,hyperinsulinemia, hypercholesterolemia, dyslipidemia, elevated bloodlevels of free fatty acids or glycerol, hyperlipidemia,hypertriglyceridemia, obesity, wound healing, tissue ischemia,atherosclerosis and hypertension. The formulations of the presentinvention can also be utilized to increase the blood levels of highdensity lipoprotein (HDL). In addition, the conditions, diseases, andmaladies collectively referenced to as “Syndrome X” or MetabolicSyndrome as detailed in Johannsson, J. Clin. Endocrinol. Metab., 82,727-34 (1997), can be treated employing the formulations of the presentinvention.

In one embodiment, the invention provides the pharmaceuticaldapagliflozin and dapagliflozin propylene glycol hydrate formulations ofthe invention for use in the treatment of type II diabetes. In anotherembodiment, the invention provides the pharmaceutical dapagliflozin anddapagliflozin propylene glycol hydrate formulations of the invention foruse in delaying the progression or onset of type II diabetes.

The invention further provides a method for treating or delaying theprogression or onset of diseases or disorders associated with SGLT2activity comprising administering to a mammalian species in need of suchtreatment a therapeutically effective amount of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention. In one embodiment, the invention provides a method fortreating type II diabetes comprising administering to a mammalianspecies in need of such treatment a therapeutically effective amount ofthe pharmaceutical dapagliflozin or dapagliflozin propylene glycolhydrate formulation of the invention. In another embodiment, theinvention provides a method for delaying the progression or onset oftype II diabetes comprising administering to a mammalian species in needof such treatment a therapeutically effective amount of thepharmaceutical dapagliflozin or dapagliflozin propylene glycol hydrateformulation of the invention.

In one embodiment, the invention provides the use of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention (including the stock granulation, capsules containingsame, and tablets thereof) in the manufacture of a medicament for thetreatment of type II diabetes. In another embodiment, the inventionprovides the use of the pharmaceutical dapagliflozin or dapagliflozinpropylene glycol hydrate formulation of the invention in the manufactureof a medicament for delaying the progression or onset of type IIdiabetes. The invention also provides the pharmaceutical dapagliflozinor dapagliflozin propylene glycol hydrate formulation of the inventionfor use in therapy in treating or delaying the progression or onset oftype H diabetes.

Other therapeutic agent(s) suitable for combination with theformulations of the present invention include, but are not limited to,known therapeutic agents useful in the treatment of the aforementioneddisorders associated with SGLT2 activity including: anti-diabeticagents; anti-hyperglycemic agents; hypolipidemic or lipid loweringagents; anti-obesity agents; anti-hypertensive agents and appetitesuppressants.

The invention further provides a method for treating or delaying theprogression or onset of diseases or disorders associated with SGLT2activity comprising administering to a mammalian species in need of suchtreatment a therapeutically effective amount of the pharmaceuticalformulation of the invention and one or more of the following:anti-diabetic agent(s), anti-hyperglycemic agent(s); hypolipidemic orlipid lowering agent(s); anti-obesity agent(s); anti-hypertensiveagent(s) and appetite suppressant(s).

In one embodiment, the invention provides a method for treating type IIdiabetes comprising administering to a mammalian species in need of suchtreatment a therapeutically effective amount of the pharmaceuticalformulation of the invention and one or more anti-diabetic agent(s). Inanother embodiment, the invention provides a method for delaying theprogression or onset of type II diabetes comprising administering to amammalian species in need of such treatment a therapeutically effectiveamount of the pharmaceutical formulation of the invention and one ormore anti-diabetic agent(s).

In another embodiment, the invention provides a method for treating ordelaying the progression or onset of type II diabetes comprisingadministering to a mammalian species in need of such treatment atherapeutically effective amount of the pharmaceutical formulation ofthe invention and one or more of the following: anti-hyperglycemicagent(s); hypolipidemic or lipid lowering agent(s); anti-obesityagent(s); anti-hypertensive agent(s) and appetite suppressant(s). Forexample, the invention provides a method for treating or delaying theprogression or onset of type II diabetes comprising administering to amammalian species in need of such treatment a therapeutically effectiveamount of a pharmaceutical formulation of the invention and ananti-hyperglycemic agent(s). In another embodiment, the inventionprovides a method for treating or delaying the progression or onset oftype II diabetes comprising administering to a mammalian species in needof such treatment a therapeutically effective amount of a pharmaceuticalformulation of the invention and a hypolipidemic agent(s). In anotherembodiment, the invention provides a method for treating or delaying theprogression or onset of type II diabetes comprising administering to amammalian species in need of such treatment a therapeutically effectiveamount of a pharmaceutical formulation of the invention and ananti-obesity agent(s). In another embodiment, the invention provides amethod for treating or delaying the progression or onset of type IIdiabetes comprising administering to a mammalian species in need of suchtreatment a therapeutically effective amount of a pharmaceuticalformulation of the invention and an anti-hypertensive agent(s). Inanother embodiment, the invention provides a method for treating ordelaying the progression or onset of type II diabetes comprisingadministering to a mammalian species in need of such treatment atherapeutically effective amount of a pharmaceutical formulation of theinvention and an appetite suppressant(s).

The invention provides the use of the pharmaceutical dapagliflozin ordapagliflozin propylene glycol hydrate formulations of the invention(including the stock granulation, capsules containing same, and tabletsthereof) in the manufacture of a medicament for the treatment ofdiseases or disorders associated with SGLT2 activity, for example, TypeI and Type II diabetes; impaired glucose tolerance; insulin resistance;and diabetic complications, such as nephropathy, retinopathy, neuropathyand cataracts; hyperglycemia; hyperinsulinemia; hypercholesterolemia;dyslipidemia; elevated blood levels of free fatty acids or glycerol;hyperlipidemia; hypertriglyceridemia; obesity; wound healing; tissueischemia; atherosclerosis; hypertension; and Syndrome X or MetabolicSyndrome.

The invention provides the use of the combination of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulations ofthe invention and one or more agents selected from the group consistingof anti-diabetic agents, anti-hyperglycemic agents, hypolipidemic orlipid lowering agents, anti-obesity agents, anti-hypertensive agents,and appetite suppressants as a medicament for the treatment of diseasesor disorders associated with SGLT2 activity, for example, Type I andType II diabetes; impaired glucose tolerance; insulin resistance; anddiabetic complications, such as nephropathy, retinopathy, neuropathy andcataracts; hyperglycemia; hyperinsulinemia; hypercholesterolemia;dyslipidemia; elevated blood levels of free fatty acids or glycerol;hyperlipidemia; hypertriglyceridemia; obesity; wound healing; tissueischemia; atherosclerosis; hypertension; and Syndrome X or MetabolicSyndrome.

In one embodiment, the invention provides the combination of thepharmaceutical dapagliflozin or dapagliflozin propylene glycol hydrateformulation of the invention and one or more anti-diabetic agents as amedicament for the treatment of type II diabetes. In another embodiment,the invention provides the combination of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention and one or more anti-diabetic agents as a medicament fordelaying the progression or onset of type II diabetes. In anotherembodiment, the invention provides the combination of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention and one or more anti-hyperglycemic agents as a medicamentfor the treatment of type II diabetes. In another embodiment, theinvention provides the combination of the pharmaceutical dapagliflozinor dapagliflozin propylene glycol hydrate formulation of the inventionand one or more anti-hyperglycemic agents as a medicament for delayingthe progression or onset of type II diabetes. In another embodiment, theinvention provides the combination of the pharmaceutical dapagliflozinor dapagliflozin propylene glycol hydrate formulation of the inventionand one or more hypolipidemic agents or lipid-lowering agents as amedicament for the treatment of type II diabetes. In another embodiment,the invention provides the combination of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention and one or more hypolipidemic agents or lipid-loweringagents as a medicament for delaying the progression or onset of type IIdiabetes. In another embodiment, the invention provides the combinationof the pharmaceutical dapagliflozin or dapagliflozin propylene glycolhydrate formulation of the invention and one or more anti-obesity agentsas a medicament for the treatment of type II diabetes. In anotherembodiment, the invention provides the combination of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention and one or more anti-obesity agents as a medicament fordelaying the progression or onset of type II diabetes. In anotherembodiment, the invention provides the combination of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention and one or more anti-hypertensive agents as a medicamentfor the treatment of type II diabetes. In another embodiment, theinvention provides the combination of the pharmaceutical dapagliflozinor dapagliflozin propylene glycol hydrate formulation of the inventionand one or more anti-hypertensive agents as a medicament for delayingthe progression or onset of type II diabetes. In another embodiment, theinvention provides the combination of the pharmaceutical dapagliflozinor dapagliflozin propylene glycol hydrate formulation of the inventionand one or more appetite suppressants as a medicament for the treatmentof type II diabetes. In another embodiment, the invention provides thecombination of the pharmaceutical dapagliflozin or dapagliflozinpropylene glycol hydrate formulation of the invention and one or moreappetite suppressants as a medicament for delaying the progression oronset of type II diabetes.

The invention provides the use of the pharmaceutical dapagliflozin ordapagliflozin propylene glycol hydrate formulation of the invention inthe manufacture of a medicament for treating or delaying the progressionor onset of Type I and Type II diabetes, impaired glucose tolerance,insulin resistance, nephropathy, retinopathy, neuropathy, cataracts,hyperglycemia, hyperinsulinemia, hypercholesterolemia, dyslipidemia,elevated blood levels of free fatty acids or glycerol, hyperlipidemia,hypertriglyceridemia, obesity, wound healing, tissue ischemia,atherosclerosis, hypertension, or Syndrome X (Metabolic Syndrome), inwhich such treatment comprises a combination with one or more agentsselected from the group consisting of anti-diabetic agents,anti-hyperglycemic agents, hypolipidemic or lipid lowering agents,anti-obesity agents, anti-hypertensive agents, and appetitesuppressants, for concurrent or sequential use, in any order.

In one embodiment, the invention provides the use of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention in the manufacture of a medicament for the treatment oftype II diabetes, in which such treatment comprises a combination withone or more anti-diabetic agents, for concurrent or sequential use, inany order. In another embodiment, the invention provides the use of thepharmaceutical dapagliflozin or dapagliflozin propylene glycol hydrateformulation of the invention in the manufacture of a medicament fordelaying the progression or onset of type II diabetes, in which suchtreatment comprises a combination with one or more anti-diabetic agents,for concurrent or sequential use, in any order. In another embodiment,the invention provides the use of the pharmaceutical dapagliflozin ordapagliflozin propylene glycol hydrate formulation of the invention inthe manufacture of a medicament for the treatment of type II diabetes,in which such treatment comprises a combination with one or moreanti-hyperglycemic agents, for concurrent or sequential use, in anyorder. In another embodiment, the invention provides the use of thepharmaceutical dapagliflozin or dapagliflozin propylene glycol hydrateformulation of the invention in the manufacture of a medicament fordelaying the progression or onset of type II diabetes, in which suchtreatment comprises a combination with one or more anti-hyperglycemicagents, for concurrent or sequential use, in any order. In anotherembodiment, the invention provides the use of the pharmaceuticaldapagliflozin or dapagliflozin propylene glycol hydrate formulation ofthe invention in the manufacture of a medicament for the treatment oftype II diabetes, in which such treatment comprises a combination withone or more hypolipidemic agent or lipid-lowering agents, for concurrentor sequential use, in any order. In another embodiment, the inventionprovides the use of the pharmaceutical dapagliflozin or dapagliflozinpropylene glycol hydrate formulation of the invention in the manufactureof a medicament for delaying the progression or onset of type IIdiabetes, in which such treatment comprises a combination with one ormore hypolipidemic agents or lipid-lowering agents, for concurrent orsequential use, in any order. In another embodiment, the inventionprovides the use of the pharmaceutical dapagliflozin or dapagliflozinpropylene glycol hydrate formulation of the invention in the manufactureof a medicament for the treatment of type II diabetes, in which suchtreatment comprises a combination with one or more anti-obesity agents,for concurrent or sequential use, in any order. In another embodiment,the invention provides the use of the pharmaceutical dapagliflozin ordapagliflozin propylene glycol hydrate formulation of the invention inthe manufacture of a medicament for delaying the progression or onset oftype II diabetes, in which such treatment comprises a combination withone or more anti-obesity agents, for concurrent or sequential use, inany order. In another embodiment, the invention provides the use of thepharmaceutical dapagliflozin or dapagliflozin propylene glycol hydrateformulation of the invention in the manufacture of a medicament for thetreatment of type II diabetes, in which such treatment comprises acombination with one or more anti-hypertensive agents, for concurrent orsequential use, in any order. In another embodiment, the inventionprovides the use of the pharmaceutical dapagliflozin or dapagliflozinpropylene glycol hydrate formulation of the invention in the manufactureof a medicament for delaying the progression or onset of type IIdiabetes, in which such treatment comprises a combination with one ormore anti-hypertensive agents, for concurrent or sequential use, in anyorder. In another embodiment, the invention provides the use of thepharmaceutical dapagliflozin or dapagliflozin propylene glycol hydrateformulation of the invention in the manufacture of a medicament for thetreatment of type II diabetes, in which such treatment comprises acombination with one or more appetite suppressants, for concurrent orsequential use, in any order. In another embodiment, the inventionprovides the use of the pharmaceutical dapagliflozin or dapagliflozinpropylene glycol hydrate formulation of the invention in the manufactureof a medicament for delaying the progression or onset of type IIdiabetes, in which such treatment comprises a combination with one ormore appetite suppressants, for concurrent or sequential use, in anyorder.

The formulations of the invention in the form of capsules or tabletscontaining dapagliflozin or dapagliflozin propylene glycol hydrate canbe administered in dosages of about 0.1 mg to about 750 mg per day, insingle or divided doses or multiple doses which can be administered 1 to4 times daily. In one embodiment, the formulations of the invention inthe form of capsules or tablets containing dapagliflozin ordapagliflozin propylene glycol hydrate is administered in dosages ofabout 0.2 mg to about 600 mg per day, in single or divided doses ormultiple doses which can be administered 1 to 4 times daily. In anotherembodiment, the formulations of the invention in the form of capsules ortablets containing dapagliflozin or dapagliflozin propylene glycolhydrate is administered in dosages of from about 0.5 mg to about 100 mgper day, in single or divided doses or multiple doses which can beadministered 1 to 4 times daily.

The present invention includes within its scope pharmaceuticalformulations containing, as an active ingredient, a therapeuticallyeffective amount of dapagliflozin or dapagliflozin propylene glycolhydrate, alone or in combination with a pharmaceutical carrier ordiluent as described. Optionally, the formulations of the presentinvention can be utilized as an individual treatment, or utilized incombination with one or more other therapeutic agent(s) in the samedosage form (fixed dosage) or separate dosage forms.

Other therapeutic agent(s) suitable for combination with theformulations of the present invention include, but are not limited to,known therapeutic agents useful in the treatment of the aforementioneddisorders including: anti-diabetic agents; anti-hyperglycemic agents;hypolipidemic/lipid lowering agents; anti-obesity agents;anti-hypertensive agents and appetite suppressants.

Examples of suitable anti-diabetic agents for use in combination withthe formulations of the present invention include, but are not limitedto, biguanides (e.g., metformin or phenformin), glucosidase inhibitors(e.g., acarbose or miglitol), insulins (including insulin secretagoguesor insulin sensitizers), meglitinides (e.g., repaglinide), sulfonylureas(e.g., glimepiride, glyburide, gliclazide, chlorpropamide andglipizide), biguanide/glyburide combinations (e.g., Glucovance®),thiazolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, glycogen phosphorylase inhibitors, inhibitors of fatty acidbinding protein (aP2), glucagon-like peptide-1 (GLP-1) and otheragonists of the GLP-1 receptor, and dipeptidyl peptidase IV (DPP4)inhibitors.

Other suitable thiazolidinediones include, but are not limited to,MCC-555 (disclosed in U.S. Pat. No. 5,594,016, Mitsubishi), faraglitazar(GI-262570, Glaxo-Wellcome), englitazone (CP-68722, Pfizer) ordarglitazone (CP-86325, Pfizer; isaglitazone, MIT/Johnson& Johnson),reglitazar (JTT-501, (JPNT/Pharmacia & Upjohn), rivoglitazone (R-119702,Sankyo/WL), liraglutide (NN-2344, Dr. Reddy/NN), and(Z)-1,4-bis-4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl-methyl)]phenoxybut-2-ene(YM-440, Yamanouchi).

Examples of PPAR-alpha agonists, PPAR-gamma agonists and PPARalpha/gamma dual agonists include, but are not limited to, muraglitazar,peliglitazar, tesaglitazar AR-HO39242 (Astra/Zeneca), GW-501516(Glaxo-Wellcome), KRP297 (Kyorin Merck), as well as those disclosed byMurakami et al, “A Novel Insulin Sensitizer Acts As a Coligand forPeroxisome Proliferation—Activated Receptor Alpha (PPAR alpha) and PPARgamma. Effect on PPAR alpha Activation on Abnormal Lipid Metabolism inLiver of Zucker Fatty Rats”, Diabetes 47, 1841-1847 (1998); WO 01/21602and in U.S. Pat. Nos. 6,414,002 and 6,653,314, the disclosures of whichare incorporated herein by reference in their entireties, employingdosages as set out therein. In one embodiment, the compounds designatedas preferred in the cited references are preferred for use herein.

Suitable aP2 inhibitors include, but are not limited to, those disclosedin U.S. application Ser. No. 09/391,053, filed Sep. 7, 1999, and in U.S.Pat. No. 6,548,529, the disclosures of which are incorporated herein byreference in their entireties, employing dosages as set out therein.

Suitable DPP4 inhibitors include, but are not limited to, thosedisclosed in WO99/38501, WO99/46272, WO99/67279 (PROBIODRUG), WO99/67278(PROBIODRUG), WO99/61431 (PROBIODRUG), NVP-DPP728A(1-[[[2-[(5-cyanopyridin-2-yl)amino]ethyl]amino]acetyl]-2-cyano-(S)-pyrrolidine)(Novartis) as disclosed by Hughes et al, Biochemistry, 38(36),11597-11603, 1999, TSL-225(tryptophyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (disclosedby Yamada et al, Bioorg. & Med. Chem. Lett. 8 (1998) 1537-1540),2-cyanopyrrolidides and 4-cyanopyrrolidides, as disclosed by Ashworth etal, Bioorg. & Med. Chem. Lett., Vol. 6, No. 22, pp 1163-1166 and2745-2748 (1996), the compounds disclosed in U.S. application Ser. No.10/899,641, WO 01/68603 and U.S. Pat. No. 6,395,767, all of which areincorporated herein by reference in their entireties, employing dosagesas set out in the above references. In one embodiment, the DPP4inhibitor is saxagliptin.

Other suitable meglitinides include nateglinide (Novartis) or KAD1229(PF/Kissei).

Examples of suitable anti-hyperglycemic agents for use in combinationwith the formulations of the present invention include, but are notlimited to, glucagon-like peptide-1 (GLP-1) such as GLP-1(1-36) amide,GLP-1(7-36) amide, GLP-1(7-37) (as disclosed in U.S. Pat. No. 5,614,492,incorporated herein by reference in its entirety), as well as exenatide(Amylin/Lilly), LY-315902 (Lilly), MK-0431 (Merck), liraglutide(NovoNordisk), ZP-10 (Zealand Pharmaceuticals A/S), CJC-1131 (ConjuchemInc), and the compounds disclosed in WO 03/033671, incorporated hereinby reference in its entirety.

Examples of suitable hypolipidemic/lipid lowering agents for use incombination with the formulations of the present invention include oneor more MTP inhibitors, HMG CoA reductase inhibitors, squalenesynthetase inhibitors, fibric acid derivatives, ACAT inhibitors,lipoxygenase inhibitors, cholesterol absorption inhibitors, ilealNa⁺/bile acid co-transporter inhibitors, up-regulators of LDL receptoractivity, bile acid sequestrants, cholesterol ester transfer protein(e.g., CETP inhibitors, such as torcetrapib (CP-529414, Pfizer) andJTT-705 (Akros Pharma)), PPAR agonists (as described above) and/ornicotinic acid and derivatives thereof. The hypolipidemic agent can bean up-regulator of LD2 receptor activity, such as1(3H)-isobenzofuranone,3-(13-hydroxy-10-oxotetradecyl)-5,7-dimethoxy-(MD-700, TaishoPharmaceutical Co. Ltd) and cholestan-3-ol,4-(2-propenyl)-(3a,4a,5a)-(LY295427, Eli Lilly). Preferred hypolipidemicagents include pravastatin, lovastatin, simvastatin, atorvastatin,fluvastatin, cerivastatin, atavastatin and rosuvastatin (ZD-4522), forexample.

Examples of MTP inhibitors that can be employed as described aboveinclude, but are not limited to, those disclosed in U.S. Pat. Nos.5,595,872, 5,739,135, 5,712,279, 5,760,246, 5,827,875, 5,885,983 and5,962,440, all of which are incorporated herein by reference in theirentireties.

Examples of HMG CoA reductase inhibitors that can be employed incombination with the formulations of the invention include, but are notlimited to, mevastatin and related compounds, as disclosed in U.S. Pat.No. 3,983,140, lovastatin (mevinolin) and related compounds, asdisclosed in U.S. Pat. No. 4,231,938, pravastatin and related compounds,such as disclosed in U.S. Pat. No. 4,346,227, simvastatin and relatedcompounds, as disclosed in U.S. Pat. Nos. 4,448,784 and 4,450,171. Othersuitable HMG CoA reductase inhibitors that can be employed hereininclude, but are not limited to, fluvastatin, disclosed in U.S. Pat. No.5,354,772, cerivastatin, as disclosed in U.S. Pat. Nos. 5,006,530 and5,177,080, atorvastatin, as disclosed in U.S. Pat. Nos. 4,681,893,5,273,995, 5,385,929 and 5,686,104, atavastatin (Nissan/Sankyo'snisvastatin (NK-104)), as disclosed in U.S. Pat. No. 5,011,930,rosuvastatin (Shionogi-Astra/Zeneca (ZD-4522)), as disclosed in U.S.Pat. No. 5,260,440, and related statin compounds disclosed in U.S. Pat.No. 5,753,675, pyrazole analogs of mevalonolactone derivatives, asdisclosed in U.S. Pat. No. 4,613,610, indene analogs of mevalonolactonederivatives, as disclosed in PCT application WO 86/03488,642-(substituted-pyrrol-1-yl)-alkyl)pyran-2-ones and derivativesthereof, as disclosed in U.S. Pat. No. 4,647,576, Searle's SC-45355 (a3-substituted pentanedioic acid derivative) dichloroacetate, imidazoleanalogs of mevalonolactone, as disclosed in PCT application WO 86/07054,3-carboxy-2-hydroxy-propane-phosphonic acid derivatives, as disclosed inFrench Patent No. 2,596,393, 2,3-disubstituted pyrrole, furan andthiophene derivatives, as disclosed in European Patent Application No.0221025, naphthyl analogs of mevalonolactone, as disclosed in U.S. Pat.No. 4,686,237, octahydronaphthalenes, such as disclosed in U.S. Pat. No.4,499,289, keto analogs of mevinolin (lovastatin), as disclosed inEuropean Patent Application No. 0142146 A2, and quinoline and pyridinederivatives, as disclosed in U.S. Pat. Nos. 5,506,219 and 5,691,322. Allof the cited references are incorporated herein by reference in theirentireties. In addition, phosphinic acid compounds useful in inhibitingHMG CoA reductase, such as those disclosed in GB 2205837, are suitablefor use in combination with the formulations of the present invention.

Examples of squalene synthetase inhibitors suitable for use hereininclude, but are not limited to, α-phosphono-sulfonates disclosed inU.S. Pat. No. 5,712,396, those disclosed by Biller et al., J. Med.Chem., 1988, Vol. 31, No. 10, pp. 1869-1871, including isoprenoid(phosphinyl-methyl)phosphonates, as well as other known squalenesynthetase inhibitors, for example, as disclosed in U.S. Pat. Nos.4,871,721 and 4,924,024 and in Biller, S. A., Neuenschwander, K.,Ponpipom, M. M., and Poulter, C. D., Current Pharmaceutical Design, 2,1-40 (1996). Other squalene synthetase inhibitors suitable for useherein include the terpenoid pyrophosphates disclosed by P. Ortiz deMontellano et al, J. Med. Chem., 1977, 20, 243-249; the farnesyldiphosphate analog A and presqualene pyrophosphate (PSQ-PP) analogs asdisclosed by Corey and Volante, J. Am. Chem. Soc., 1976, 98, 1291-1293;phosphinylphosphonates reported by McClard, R. W. et al, J.A.C.S., 1987,109, 5544; and cyclopropanes reported by Capson, T. L., PhDdissertation, June, 1987, Dept. Med. Chem. U of Utah, Abstract, Table ofContents, pp 16, 17, 40-43, 48-51, Summary. All of the cited referencesare incorporated herein by reference in their entireties.

Examples of fibric acid derivatives that can be employed in combinationthe formulations of the invention include, but are not limited to,fenofibrate, gemfibrozil, clofibrate, bezafibrate, ciprofibrate,clinofibrate and the like, probucol, and related compounds, as disclosedin U.S. Pat. No. 3,674,836, bile acid sequestrants, such ascholestyramine, colestipol and DEAE-Sephadex (Secholex®, Policexide®),as well as lipostabil (Rhone-Poulenc), Eisai E-5050 (an N-substitutedethanolamine derivative), imanixil (HOE-402), tetrahydrolipstatin (THL),istigmastanylphos-phorylcholine (SPC, Roche), aminocyclodextrin (TanabeSeiyoku), Ajinomoto AJ-814 (azulene derivative), melinamide (Sumitomo),Sandoz 58-035, American Cyanamid CL-277,082 and CL-283,546(disubstituted urea derivatives), nicotinic acid, acipimox, acifran,neomycin, p-aminosalicylic acid, aspirin, poly(diallylmethylamine)derivatives, such as disclosed in U.S. Pat. No. 4,759,923, quaternaryamine poly(diallyldimethylammonium chloride) and ionenes, such asdisclosed in U.S. Pat. No. 4,027,009, and other known serum cholesterollowering agents. In one embodiment, the fibric acid derivative isprobucol or gemfibrozil. All of the cited references are incorporatedherein by reference in their entireties.

Examples of ACAT inhibitors that can be employed in combination with theformulations of the invention include, but are not limited to, thosedisclosed in Drugs of the Future 24, 9-15 (1999), (Avasimibe); “The ACATinhibitor, CI-1011 is effective in the prevention and regression ofaortic fatty streak area in hamsters”, Nicolosi et al, Atherosclerosis(Shannon, Irel). (1998), 137(1), 77-85; “The pharmacological profile ofFCE 27677: a novel ACAT inhibitor with potent hypolipidemic activitymediated by selective suppression of the hepatic secretion ofApoB100-containing lipoprotein”, Ghiselli, Giancarlo, Cardiovasc. DrugRev. (1998), 16(1), 16-30; “RP 73163: a bioavailablealkylsulfinyl-diphenylimidazole ACAT inhibitor”, Smith, C., et al,Bioorg. Med. Chem. Lett. (1996), 6(1), 47-50; “ACAT inhibitors:physiologic mechanisms for hypolipidemic and anti-atheroscleroticactivities in experimental animals”, Krause et al, Editor(s): Ruffolo,Robert R., Jr.; Hollinger, Mannfred A., Inflammation: Mediators Pathways(1995), 173-98, Publisher: CRC, Boca Raton, Fla.; “ACAT inhibitors:potential anti-atherosclerotic agents”, Sliskovic et al, Curr. Med.Chem. (1994), 1(3), 204-25; “Inhibitors of acyl-CoA:cholesterol O-acyltransferase (ACAT) as hypocholesterolemic agents. The firstwater-soluble ACAT inhibitor with lipid-regulating activity. Inhibitorsof acyl-CoA: cholesterol acyltransferase (ACAT). Development of a seriesof substituted N-phenyl-N′-[(1-phenylcyclopentyl)methyl]ureas withenhanced hypocholesterolemic activity”, Stout et al, Chemtracts: Org.Chem. (1995), 8(6), 359-62, or TS-962 (Taisho Pharmaceutical Co. Ltd).All of the cited references are incorporated herein by reference intheir entireties.

Examples of suitable cholesterol absorption inhibitors for use incombination with the formulations of the invention include, but are notlimited to, SCH48461 (Schering-Plough), as well as those disclosed inAtherosclerosis 115, 45-63 (1995) and J. Med. Chem. 41, 973 (1998),incorporated herein by reference in its entirety.

Examples of suitable ileal Na⁺/bile acid co-transporter inhibitors foruse in combination with the formulations of the invention include, butare not limited to, compounds as disclosed in Drugs of the Future, 24,425-430 (1999), incorporated herein by reference in its entirety.

Examples of lipoxygenase inhibitors that can be employed in combinationwith the formulations of the invention include, but are not limited to,15-lipoxygenase (15-LO) inhibitors, such as benzimidazole derivatives,as disclosed in WO 97/12615, 15-LO inhibitors, as disclosed in WO97/12613, isothiazolones, as disclosed in WO 96/38144, and 15-LOinhibitors, as disclosed by Sendobry et al “Attenuation of diet-inducedatherosclerosis in rabbits with a highly selective 15-lipoxygenaseinhibitor lacking significant antioxidant properties”, Brit. J.Pharmacology (1997) 120, 1199-1206, and Cornicelli et al.,“15-Lipoxygenase and its Inhibition: A Novel Therapeutic Target forVascular Disease”, Current Pharmaceutical Design, 1999, 5, 11-20. All ofthe cited references are incorporated herein by reference in theirentireties.

Examples of suitable anti-hypertensive agents for use in combinationwith the formulations of the present invention include, but are notlimited to, beta adrenergic blockers, calcium channel blockers (L-typeand T-type; e.g. diltiazem, verapamil, nifedipine, amlodipine andmybefradil), diuretics (e.g., chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetanide, triamtrenene, amiloride, spironolactone), renin inhibitors,ACE inhibitors (e.g., captopril, zofenopril, fosinopril, enalapril,ceranopril, cilazopril, delapril, pentopril, quinapril, ramipril,lisinopril), AT-1 receptor antagonists (e.g., losartan, irbesartan,valsartan), ET receptor antagonists (e.g., sitaxsentan, atrsentan andcompounds disclosed in U.S. Pat. Nos. 5,612,359 and 6,043,265), DualET/AII antagonist (e.g., compounds disclosed in WO 00/01389), neutralendopeptidase (NEP) inhibitors, vasopepsidase inhibitors (dual NEP-ACEinhibitors) (e.g., omapatrilat and gemopatrilat), and nitrates. All ofthe cited references are incorporated herein by reference in theirentireties.

Examples of suitable anti-obesity agents for use in combination with theformulations of the present invention include, but are not limited to,beta 3 adrenergic agonists, lipase inhibitors, serotonin (and dopamine)reuptake inhibitors, thyroid receptor beta drugs, 5HT2C agonists, (suchas Arena APD-356); MCHR1 antagonists, such as Synaptic SNAP-7941 andTakeda T-226926, melanocortin receptor (MC4R) agonists,melanin-concentrating hormone receptor (MCHR) antagonists (such asSynaptic SNAP-7941 and Takeda T-226926), galanin receptor modulators,orexin antagonists, CCK agonists, NPY1 or NPY5 antagonist, NPY2 and NPY4modulators, corticotropin releasing factor agonists, histaminereceptor-3 (H3) modulators, 11-beta-HSD-1 inhibitors, adinopectinreceptor modulators, monoamine reuptake inhibitors or releasing agents,ciliary neurotrophic factors (CNTF, such as AXOKINE® by Regeneron), BDNF(brain-derived neurotrophic factor), leptin and leptin receptormodulators, cannabinoid-1 receptor antagonists (such as SR-141716(Sanofi) or SLV-319 (Solvay)), and anorectic agents.

Beta 3 adrenergic agonists that can be optionally employed incombination with formulations of the present invention include, but arenot limited to, AJ9677 (Takeda/Dainippon), L750355 (Merck), CP331648(Pfizer,) or other known beta 3 agonists, as disclosed in U.S. Pat. Nos.5,541,204, 5,770,615, 5,491,134, 5,776,983 and 5,488,064, all of whichare incorporated herein by reference in their entireties.

Examples of lipase inhibitors that can be employed in combination withformulations of the present invention include, but are not limited to,orlistat and ATL-962 (Alizyme).

Serotonin (and dopamine) reuptake inhibitors (or serotonin receptoragonists) that can be employed in combination with the formulations ofthe present invention include, but are not limited to, BVT-933(Biovitrum), sibutramine, topiramate (Johnson & Johnson) and axokine(Regeneron).

Examples of thyroid receptor beta compounds that can be employed incombination with formulations of the present invention include, but arenot limited to, thyroid receptor ligands, such as those disclosed in WO97/21993 (U. Cal SF), WO 99/00353 (KaroBio) and WO 00/039077 (KaroBio),incorporated herein by reference it their entireties.

Examples of monoamine reuptake inhibitors that can be employed incombination with the formulations of the present invention include, butare not limited to, fenfluramine, dexfenfluramine, fluvoxamine,fluoxetine, paroxetine, sertraline, chlorphentermine, cloforex,clortermine, picilorex, sibutramine, dexamphetamine, phentermine,phenylpropanolamine and mazindol.

Anorectic agents that can be employed in combination with theformulations of the present invention include, but are not limited to,topiramate (Johnson & Johnson), dexamphetamine, phentermine,phenylpropanolamine and mazindol.

The aforementioned patents and patent applications are incorporatedherein by reference.

Where any of the formulations of the invention are used in combinationwith other therapeutic agent(s), the other therapeutic agent(s) can beused, for example, in the amounts indicated in the Physician's DeskReference, as in the cited patents and patent applications set outabove, or as otherwise known and used by one of ordinary skill in theart.

Where any of the formulations of the invention are used in combinationwith other therapeutic agent(s), each of the compounds of thecombination can be administered simultaneously or sequentially and inany order, and the components can be administered separately or as afixed combination, in jointly therapeutically effective amounts, forexample, in daily dosages as described herein. In one embodiment of theinvention, a fixed combination of the invention can be prepared bymixing a dry granulation of the dapagliflozin or dapagliflozin propyleneglycol hydrate formulation of the invention and a dry granulation of theother therapeutic agent(s) and filling the mixture into capsules ofdesired size, shape, color, or other characteristics, or compressed toform tablets.

While this invention has been particularly shown and described withreferences to preferred embodiments thereof, it will be understood bythose skilled in the art that various changes in form and details may bemade therein without departing from the scope of the inventionencompassed by the appended claims. It will also be clear that theinvention may be practiced otherwise than as particularly described inthe foregoing description and examples. Numerous modifications andvariations of the present invention are possible in light of the aboveteachings and, therefore, are within the scope of the appended claims.

The following examples are provided to describe the invention in furtherdetail. These examples, which set forth the best mode presentlycontemplated for carrying out the invention, are intended to illustrateand not to limit the invention.

EXAMPLES

The following working Examples are illustrative of the presentinvention. All temperatures are expressed in degrees Centigrade unlessotherwise indicated.

Example 1 Preparation of Dapagliflozin (Compound I)

The preparation of compounds of structure I is generally described inU.S. Pat. No. 6,414,126, and specifically described in Scheme 1 andExample 1 of U.S. Pat. No. 5,515,117, both of which are incorporated byreference herein in their entireties. Stable forms of compounds ofstructure (I) can be crystallized as solvates (e.g., hydrates) orcomplexes.

Example 2A Preparation of Dapagliflozin (S)-Propylene Glycol Hydrate(Ia)

The preparation of structure Ia is described and depicted schematicallybelow.

Compound A can be prepared as described in Example 1, Part E of U.S.Pat. No. 6,515,117.

A 10-L glass reactor equipped with a thermocouple and a nitrogen inletwas charged with MeOH (1.25 L), deionized water (3.6 L) followed by 50%aqueous NaOH (205.9 ml, 3.899 mol). The residual solution of NaOH in themeasuring cylinder was transferred with water (94 ml) to the reactionvessel. Compound A (503.11 g, 0.872 mol) was added and the mixture wasstirred and heated to ˜68° C. over 1.5 hour. After 1 hour, thecirculation bath temperature was lowered from 80° C. to 70° C.; internaltemperature became 65° C. After a total of 3 hours, HPLC indicatedcompletion of reaction, Compound I AP ˜99.5. (HPLC: Column: YMC ODS-A(C-18) S3, 4.6×50 mm. Solvent A: 0.2% aq. H₃PO₄. Solvent B: 90%CH₃CN/10% H₂O Start % B=0, final % B=100 Gradient time 8 min; hold time3 minutes. Integration stop time 11.0 minutes. Flow rate 2.5 ml/minute.UV wave length 220 nm.)

After the mixture was cooled to 25° C., isopropyl acetate (2.5 L) wasadded. The mixture was stirred for 10 minutes and then the aqueous layerwas separated (pH=12.5) and organic layer was washed with water (1 L).During this wash the pH of the biphasic system was adjusted to 6.0 withconcentrated HCl (5.0 ml) and then the aqueous layer was separated.Neutralization before phase split was done to prevent contamination ofthe product with NaOH. The (S)-propylene glycol structure preparedwithout neutralization was slightly basic [pH 8.3 of a suspensionsonicated in water (˜20 mg/ml)].

The organic layer was collected in a separate vessel. The reactor waswashed with water (2 L), MeOH (2 L) and flushed with nitrogen gas. Thewet solution of compound B was recharged into the reactor and(S)-propylene glycol ((S)-PG) (67.03 g, 0.872 mole) was introduced.Optionally, seed crystals of (S)-PG Ia can be added at this stage. Seedcrystals can be prepared by dissolving compound I in a solvent such asMTBE and treating the resulting solution with (S)-propylene glycol andproceeding as described above without the use of seeding.

Instantaneous crystallization produced a thick slurry. After stirringfor 1 hour, cyclohexane (2.5 L) was added rapidly over 10 minutes andthe stirring was continued for 21 hours. The product was filteredthrough a filter paper (Whatman #5, Buchner funnel 24″ diameter). Thefiltration was rapid and took about 15 minutes. The filter cake waswashed with a mixture (1:1) of MTBE/cyclohexane (2×1 L) and dried undersuction for 0.5 hour. The solid was transferred to a pyrex tray anddried under vacuum (25 mm Hg) in an oven at 25-30° C. for two days tillwater analysis by K. F. corresponded to monohydrate (3.6 wt. %). The(S)-PG product Ia was obtained (0.425 kg, yield 97%) as a snow whitesolid, mp 71° C., HPLC AP 99.7. (HPLC method: Mobile Phase A: 0.05% TFAin H₂O. Mobile Phase B: 0.05% TFA in CAN. Column: YMC Hydrosphere4.6×150 (3μ). Gradient: 30-90% B over 45 minutes, hold 5 minutes; backto 30% B and re-equilibrate for 10 min. Wavelength: 220 nm. InjectionVolume: 10 μl. Temperature: Ambient).

The (R) form of dapagliflozin can be prepared using these methods andsubstituting (S)-propylene glycol with (R)-propylene glycol.

Example 2B Preparation of Dapagliflozin (S)-Propylene Glycol Hydrate(Compound Ia)

The structure Ia can alternatively be prepared as described and depictedschematically below.

20 g of compound A was charged to a reactor at ambient temperature andpressure. 30 mL Methanol and 49.75 mL 3N NaOH were added to the reactorand the reaction mixture was heated to 80° C. or reflux, and held about2-3 hours for reaction completion<0.5 AP. The batch was cooled to 20° C.and neutralized to pH 6.0-7.5 using IN acetic acid (requires ˜1 mL/gminput).

Extraction: The product was extracted from the reaction mixture into 100mL isopropyl acetate, the aqueous phase was split away and the organicphase washed with water until conductivity<10 mS (˜4 mL/gm input). Theaqueous phase was split away.

Crystallization: 2.8 g (1.05 eq) (S)-(+)-1,2 Propanediol 96%+ was addedto the reaction mixture. The batch was seeded with 0.1 g compound Iseed. 160 mL Cyclohexane was added and the batch cooled to 5° C. Thebatch was allowed to stir at 5° C. at least 1 hour before isolation.

Isolation and Drying: Each load of isolated cake was washed with 50/50by volume isopropyl acetate/cyclohexane mixture. The cake was dried at30° C. in a vacuum oven under full vacuum. (Cake is dry whenKF=3.6%-4.1%).

-   Yield=84% (uncorrected)-   Typical purity=99.81AP-   Typical PG content=15.1-15.8% by GC

Capsules containing the SGLT2 inhibitor of Formula I (dapagliflozin) orFormula Ia (dapagliflozin (S)—Propylene glycol hydrate) were prepared instrengths of 2.5 mg (Example 3), 10 mg (Example 4) and 100 mg (Example5) as two-piece, gray opaque size #0 (2.5 mg and 10 mg) and size #00(for 100 mg) hard gelatin capsules.

Example 3 Preparation of Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Capsule, 2.5 Mg

A 25.0 mg of stock granulation was prepared containing 10% dapagliflozinor dapagliflozin propylene glycol hydrate filled in gray, opaque, size#0 capsule shell.

A. Stock Granulation Composition

Amount Ingredient (% w/w) Dapagliflozin or Dapagliflozin propyleneglycol hydrate 10.0 (Or equivalent amount of Dapagliflozin propyleneglycol hydrate) Pregelatinized Starch 15.0 Microcrystalline Cellulose68.75 Sodium Starch Glycolate 3.0 Silicon Dioxide 2.0 Magnesium Stearate1.25

The amount of dapagliflozin is theoretically equivalent to 81.29% ofdapagliflozin propylene glycol hydrate, either of which can be used. Theactual amount of dapagliflozin propylene glycol hydrate will depend onthe purity. The microcrystalline cellulose is the compensating excipientwhose amount can vary depending on the actual amount of dapagliflozinpropylene glycol hydrate and magnesium stearate used. The preferredamount of magnesium stearate is 1.25% (w/w). A useful range is1.25-1.50% (w/w).

The stock granulation of Part A and the Example 3 capsules were preparedaccording to the following procedures.

B. Example 3 Stock Granulation Procedure

-   -   1. Screen dapagliflozin or dapagliflozin propylene glycol        hydrate.    -   2. Screen silicon dioxide.    -   3. Mix silicon dioxide with dapagliflozin or dapagliflozin        propylene glycol hydrate in a suitable blender.    -   4. Screen pregelatinized starch and microcrystalline cellulose,        if necessary.    -   5. Add ingredients from Step 4 to a suitable blender.    -   6. Add mixture from Step 3 to the blend from Step 5, and mix.    -   7. Screen sodium starch glycolate.    -   8. Add ingredient from Step 7 to the blend from Step 6, and mix.    -   9. Screen the blend from Step 8, and mix.    -   10. Screen portion of magnesium stearate.    -   11. Add ingredient from Step 10 to the blend from Step 9, and        mix.    -   12. Densify the blend from Step 11.    -   13. Reduce the densified blend Step 12.    -   14. Screen the remaining portion of magnesium stearate.    -   15. Add ingredient from Step 14 to the granulation from Step 13,        and mix.

C. Example 3 Product: Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Capsule, 2.5 Mg

-   -   1. Fill empty capsule shells with sufficient Example 3 Part A        stock granulation for capsules (10.0%) w/w (as the non-solvated        form), to provide 2.5 mg capsules.    -   2. De-dust the capsules.

Example 4 Preparation of Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Capsule, 10 Mg

A. Stock Granulation Composition

Stock granulation composition was prepared as described in Example 3A.

B. Example 4 Stock Granulation Procedure

Stock granulation procedure was performed as described in Example 3B.

C. Example 4 Product: Dapagliflozin Capsule, 10 Mg

-   -   1. Fill empty capsule shells with Example 3 Part A stock        granulation for capsules (10.0% w/w as the non-solvated form),        to provide 10 mg capsules.    -   2. De-dust the capsules.    -   3. Weight sort the capsules.

Example 5 Preparation of Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Capsule, 100 Mg

Composition: 438.6 mg of dapagliflozin (Example 5 Part A) StockGranulation for Capsules (22.8% w/w), filled in Gray, Opaque, Size #0Capsule Shell was prepared.

A. Stock Granulation Composition

Amount Ingredient (% w/w) Dapagliflozin or Dapagliflozin propyleneglycol hydrate 22.8 (Or equivalent amount of Dapagliflozin propyleneglycol hydrate) Pregelatinized Starch 15.0 Microcrystalline Cellulose55.95 Sodium Starch Glycolate 3.0 Silicon Dioxide 2.0 Magnesium Stearate1.25

The amount of dapagliflozin is theoretically equivalent to 81.29% ofdapagliflozin propylene glycol hydrate hydrate, either of which can beused. The actual amount of dapagliflozin propylene glycol hydrate willdepend on the purity. The microcrystalline cellulose is the compensatingexcipient whose amount can vary depending on the actual amount ofdapagliflozin propylene glycol hydrate and magnesium stearate used. Thepreferred amount of magnesium stearate is 1.25% (w/w). A useful range is1.25-1.50% (w/w).

The stock granulation of Part 5A and the Example 5 capsules wereprepared according to the following procedures.

B. Stock Granulation Procedure

-   -   1. Screen silicon dioxide.    -   2. Mix silicon dioxide with dapagliflozin or dapagliflozin        propylene glycol hydrate in a suitable blender.    -   3. Screen the blend from Step 2, and mix again.    -   4. Screen pregelatinized starch and microcrystalline cellulose,        if necessary.    -   5. Add ingredients form Step 4 to the blend from Step 3, and        mix.    -   6. Screen sodium starch glycolate.    -   7. Add ingredient from Step 6 to the blend from Step 5, and mix.    -   8. Screen a portion of magnesium stearate.    -   9. Add ingredient from Step 8 to the blend from Step 7, and mix.    -   10. Densify the blend from Step 9.    -   11. Reduce the densified blend from Step 10.    -   12. Screen the remaining portion of magnesium stearate.    -   13. Add ingredient from Step 12 to the granulation from Step 11,        and mix.

C. Example 5 Product: Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Capsule, 100 Mg

-   -   1. Fill empty capsule shells with Example 5 stock granulation        for capsules (22.8% w/w as the non-solvated form).    -   2. De-dust the capsules.    -   3. Weight sort the capsules.

The formed capsules of Example 3 (2.5 mg), Example 4 (10 mg), andExample 5 (100 mg) are used in treating metabolic disorders, includingobesity.

Example 6 Treatment of Metabolic Disorders

An oral solution (0.5 mg/mL) was prepared by dissolving dapagliflozin ordapagliflozin propylene glycol hydrate in a mixture of polyethyleneglycol 400, NF and water (USP or purified water) 30:70% v/v. The oralsolution was clear and colorless.

The glucosuric effects of dapagliflozin propylene glycol hydrate resultsin significant loss of calories in the urine versus a known SGLT2inhibitor (GSK 869,682). The results of an indirect comparison of twosingle ascending dose studies of SGLT2 inhibitors is described. Theamount of glucose excretion/day in healthy subjects taking 50, 100, 200or 500 mg of GSK 869,682 was approximately 5 g, 6 g, 12 g, and 16 g,respectively. The amount of glucose excretion/day in healthy subjectstaking 5, 20, 50 or 100 mg of dapagliflozin propylene glycol hydrate wasapproximately 30 g, 55 g, 60 g, and 70 g, respectively. The results ofthe dapagliflozin propylene glycol hydrate study was further confirmedin a 14-day multiple ascending dose phase 2a study in subjects with type2 diabetes. Patients with type 2 diabetes were treated with placebo, 5mg dapagliflozin propylene glycol hydrate, 25 mg dapagliflozin propyleneglycol hydrate, or 100 mg dapagliflozin propylene glycol hydrate.Results from the 24-hour glucose excretion show that subjects taking 5mg, 25 mg, and 100 mg dapagliflozin propylene glycol hydrate hadsignificantly higher urine glucose excretion compared to subjects takingplacebo.

Diet-Induced Obesity in Rats

Obesity was induced in male Sprague-Dawley rats (mean baselineweight=220 g) via ad libitum access to 2 diets: normal diet (HarlanTeklad rat chow; 3.5 kcal/gm, 5% vegetable fat) andhigh-sucrose/high-fat diet (Research Diets D12327; 4.6 kcal/gm, 40%sucrose and 40% vegetable fat). Rats under these conditions typicallyconsume approximately 30 g/day of the high-sucrose/high-fat chow and 2g/day of the nom al Harlan Teklad rat chow. A 220-g rat given access toboth diets will weigh approximately 750 g after 10 weeks.

Acute Glucosuria Study

Dapagliflozin propylene glycol hydrate (1, 5, or 10 mg/kg) or placebo(vehicle) was orally administered to diet-induced obese (DIO) rats after24-hour baseline urine samples were collected. Urine volume and glucoseconcentration were used to determine total urine glucose loss over 24hours post dose.

Total urine glucose was determined after 24 hours administration ofdapagliflozin propylene glycol hydrate. Total glucose lost wascalculated as volume of urine×glucose concentration. The results showedthat the total amount of glucose lost over 24 hours post dose wassignificantly increased with increasing doses of dapagliflozin propyleneglycol hydrate in a dose-dependent manner.

Chronic Weight Loss Study

DIO rats were sorted into treatment groups based on body weight, totalkilocalories consumed, and body composition (via echo MRI).Dapagliflozin propylene glycol hydrate (0.5, 1, or 5 mpk) or placebo wasorally administered to DIO rats for 28 days. To assess the importance ofcompensatory over-eating in drug-treated animals, a subgroup of ratsthat received 5 mg/kg of dapagliflozin propylene glycol hydrate wasrestricted to the food intake of the placebo group. Body weight and theweight of both diets were determined daily. Respiratory quotient datawere obtained on days 2 and 15 of the study, echo MRI was obtained onday 22, and blood was collected for a fasting clinical chemistry testson day 27.

Chronically administered dapagliflozin propylene glycol hydrate(administered daily over 25 days) produced significant weight loss(p<0.05 versus vehicle) in diet-induced obese rats. If thecompound-induced overeating was prevented (dapagliflozin propyleneglycol hydrate mg/kg pair fed to vehicle group), then the weight losswas greater. Percent weight changes were calculated as daily weight—day0 weight×100.

Weight Loss in Patients with Type II Diabetes

Treatment naive type II diabetes mellitus patients, n=389, withinadequate blood glycemic control and low mean glucosuria at baselinewere given once-daily oral treatments with dapagliflozin propyleneglycol hydrate (2.5, 5, 10, 20, or 50 mgs), Metformin XR® (750 mgtitrated to 1500 mgs), or placebo over 12-weeks.

Treatment with dapagliflozin propylene glycol hydrate resulted inconsistent and sustained increases in urinary glucose excretion, risingto mean glucosuria values between 51.8 g/day to 85.0 g/day at week 12from baseline means between 5.8 grams/day to 10.9 grams/day. Meanglucosuria with placebo and metformin both remained low, 5.7 grams/dayand 5.6 grams/day respectively at week 12. A higher proportion ofpatients in each of the dapagliflozin propylene glycol hydrate groupsachieved a 5% weight reduction over those patients taking placebo. Meanpercent reductions for body weight and absolute changes in body massindex (BMI) over 12 weeks are shown in Table 111.

TABLE III Dapagliflozin-PGS Dose 2.5 mgs 5 mgs 10 mgs 20 mgs 50 mgsPlacebo Metformin n = 59 n = 58 n = 47 n = 59 n = 56 n = 54 n = 56Baseline weight 90 89 86 88 91 89 88 (kg) Mean reduction −2.7 −2.5 −2.7−3.4 −3.4 −1.2 −1.7 in weight (%) Baseline BMI 31 31 30 31 32 32 32(kg/m²) Mean reduction −0.9 −0.8 −0.8 −1.0 −1.1 −0.3 −0.5 in BMI

Example 7 Preparation of Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Tablet, 2.5 Mg

Tablets containing the SGLT2 inhibitor dapagliflozin or dapagliflozinpropylene glycol hydrate were prepared in strengths of 2.5 mg (Example7), 10 mg (Example 8) and 50 mg (Example 9) as described below.

Product: Dapagliflozin/Dapagliflozin Propylene Glycol Hydrate Tablet,2.5 Mg

A. Tablet Composition

Ingredient Amount Dapagliflozin propylene glycol hydrate 3.08 mg (Orequivalent amount of Dapagliflozin) Microcrystalline Cellulose 67.11 mgAnhydrous Lactose 25.00 mg Crospovidone 8.75 mg Croscarmellose Sodium3.75 mg Talc 12.50 mg Silicon Dioxide 2.88 mg Magnesium Stearate 1.94 mg

The amount of dapagliflozin is theoretically equivalent to 81.29% ofdapagliflozin propylene glycol hydrate, either of which can be used. Theactual amount of dapagliflozin propylene glycol hydrate will depend onthe purity. The microcrystalline cellulose is the compensating excipientwhose amount can vary depending on the actual amount of dapagliflozinpropylene glycol hydrate and magnesium stearate used. The target amountof magnesium stearate is 1.94 mg. An acceptable range is about 1.55 toabout 2.33 mg.

The stock granulation of Part 7A and the Example 7 tablets were preparedaccording to the following procedures.

B. Stock Granulation Procedure

-   -   1. Deaggregate dapagliflozin propylene glycol hydrate or        dapagliflozin and magnesium stearate separately using a suitable        screen.    -   2. Mix dapagliflozin propylene glycol hydrate or dapagliflozin        with a portion of microcrystalline cellulose in a suitable        mixer; pass through a mill; and transfer it into a suitable        blender.    -   3. “Dry Rinse” the mixer used for mixing Step 2 with a portion        of microcrystalline cellulose.    -   4. Add the blend from Step 3 to the blend from Step 2.    -   5. Mix the mixture from Step 4 with remaining microcrystalline        cellulose, portion of crospovidone, portion of croscarmellose        sodium, portion of silicon dioxide and Anhydrous Lactose.    -   6. Add talc and intragranular magnesium stearate to the mixture        from Step 5 and mix.    -   7. Compact the powder blend from Step 6.    -   8. Reduce compact from Step 7 to form granules.    -   9. Mix the granules from Step 8 with remaining amounts of        crospovidone, croscarmellose sodium and silicon dioxide.    -   10. Mix the granules from Step 9 with remaining amount of        magnesium stearate.

C. Example 7 Product: Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Tablet, 2.5 Mg

1. Setup the tabletting equipment.

2. Compress the Example 7 stock granulation into tablets.

Example 8 Preparation of Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Tablet, 10 Mg

Product: Dapagliflozin/Dapagliflozin Propylene Glycol Hydrate Tablet, 10Mg

A. Tablet Composition

Ingredient Amount Dapagliflozin propylene glycol hydrate 12.30 mg (Orequivalent amount of Dapagliflozin) Microcrystalline Cellulose 57.89 mgAnhydrous Lactose 25.00 mg Crospovidone 8.75 mg Croscarmellose Sodium3.75 mg Talc 12.50 mg Silicon Dioxide 2.88 mg Magnesium Stearate 1.94 mg

The amount of dapagliflozin is theoretically equivalent to 81.29% ofdapagliflozin propylene glycol hydrate, either of which can be used. Theactual amount of dapagliflozin propylene glycol hydrate will depend onthe purity. The microcrystalline cellulose is the compensating excipientwhose amount can vary depending on the actual amount of dapagliflozinpropylene glycol hydrate and magnesium stearate used. The target amountof magnesium stearate is 1.94 mg. An acceptable range is about 1.55 toabout 2.33 mg.

The stock granulation of Part 8A and the Example 8 tablets were preparedaccording to the following procedures.

B. Stock Granulation Procedure

-   -   1. Deaggregate dapagliflozin propylene glycol hydrate or        dapagliflozin and magnesium stearate separately using a suitable        screen.    -   2. Mix microcrystalline cellulose, dapagliflozin propylene        glycol hydrate or dapagliflozin, portion of crospovidone,        portion of croscarmellose sodium, portion of silicon dioxide and        anhydrous lactose in a suitable blender.    -   3. Add talc and intragranular magnesium stearate to the mixture        from Step 2 and mix in a suitable blender.    -   4. Compact the powder blend from Step 3.    -   5. Reduce compact from Step 4 to form granules.    -   6. Mix the granules from Step 5 with remaining amounts of        crospovidone, croscarmellose sodium and silicon dioxide.    -   7. Mix the granules from Step 6 with remaining amount of        magnesium stearate.

C. Example 8—Product: Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Tablet, 10 Mg

-   -   1. Setup the tabletting equipment.    -   2. Compress the Example 8 stock granulation into tablets.

Example 9 Preparation of Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Tablet, 50 Mg

Product: Dapagliflozin/Dapagliflozin Propylene Glycol Hydrate Tablet, 50Mg

A. Tablet Composition

Ingredient Amount Dapagliflozin propylene glycol hydrate 61.66 mg (Orequivalent amount of Dapagliflozin) Microcrystalline Cellulose 114.09 mgAnhydrous Lactose 62.60 mg Crospovidone 21.91 mg Croscarmellose Sodium9.39 mg Talc 31.30 mg Silicon Dioxide 7.20 mg Magnesium Stearate 4.85 mg

The amount of dapagliflozin is theoretically equivalent to 81.29% ofdapagliflozin propylene glycol hydrate, either of which can be used. Theactual amount of dapagliflozin propylene glycol hydrate will depend onthe purity. The microcrystalline cellulose is the compensating excipientwhose amount can vary depending on the actual amount of dapagliflozinpropylene glycol hydrate and magnesium stearate used. The target amountof magnesium stearate is 4.85 mg. An acceptable range is about 3.76 toabout 5.95 mg.

The stock granulation of Part 9A and the Example 9 tablets were preparedaccording to the following procedures.

B. Stock Granulation Procedure

-   -   1. Mix dapagliflozin propylene glycol hydrate or dapagliflozin,        microcrystalline cellulose, anhydrous lactose, crospovidone,        croscarmellose sodium, talc and silicon dioxide in a suitable        blender.    -   2. Pass the mixture from Step 1 through a suitable mill.    -   3. Determine the yield from Step 1 and calculate the amount of        magnesium stearate required.    -   4. Mix the mixture from Step 2 in a suitable blender.    -   5. Mix the mixture from Step 4 with magnesium stearate.    -   6. Dry granulate the powder blend from Step 5.    -   7. Size the granulation from Step 6.    -   8. Determine the yield based on Step 7.    -   9. Mix the granules from Step 8 with remaining amount of        crospovidone, croscarmellose sodium and silicon dioxide.    -   10. Mix the granules from Step 9 with remaining amount of        magnesium stearate.

C. Example 9 Product: Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Tablet, 50 Mg

-   -   1. Setup the tabletting equipment.    -   2. Compress the Example 9 stock granulation into tablets.

Example 10 Preparation of Dapagliflozin/Dapagliflozin Propylene GlycolHydrate TABLETS (10-, 25-, and 40 mg)

Product: Dapagliflozin/Dapagliflozin Propylene Glycol Hydrate Tablets(10 mg, 25 mg, and 40 mg)

A. Granulation Composition (% w/w)

Ingredient Formulation % w/w Dapagliflozin propylene glycol hydrate 9.84(Or equivalent amount of Dapagliflozin) Microcrystalline Cellulose 63.91Anhydrous Lactose 20 Crospovidone 4 Silicon Dioxide 1.5 MagnesiumStearate 0.75

B. Stock Granulation Procedure:

-   -   1. Mix dapagliflozin propylene glycol hydrate or dapagliflozin        with microcrystalline cellulose.    -   2. Pass the mixture from step 1 through a suitable mill.    -   3. Mix the blend from step 2 with microcrystalline cellulose,        lactose anhydrous, crospovidone, and silicon dioxide.    -   4. Mix the blend from step 3 with magnesium stearate.    -   5. Dry granulate the powder blend from Step 4.    -   6. Size the granulation from Step 5 using appropriate sieve(s).    -   7. Determine the yield based on step 6.    -   8. Mix the granules from Step 7 with remaining amount of        crospovidone, and silicon dioxide.    -   9. Mix granules from step 8 with remaining amount of magnesium        stearate.

Tablets or capsules of various strengths (8-50 mg) can be prepared usingdifferent weights of this granulation using tabletting proceduredescribed above.

Tabletting/capsule filling operations: Same as other formulationsprovided herein.

Film coating: Hydroxypropylmethyl cellulose, titanium dioxide,polyethylene glycol, and colorant. Alternative film coating: Polyvinylalcohol (PVA), titanium dioxide, polyethylene glycol, talc, andcolorant.

Example 11 Preparation of Dapagliflozin/Dapagliflozin Propylene GlycolHydrate Tablets (1, 2.5, 5, 10 mg)

Product: Dapagliflozin/Dapagliflozin Propylene Glycol Hydrate Tablets 1,2.5, 5, 10 Mg

A. Granulation Composition

1 mg 2.5 mg 5 mg 10 mg Ingredient Tablet Tablet Tablet TabletDapagliflozin propylene glycol 1.23 mg 3.075 mg 6.15 mg 12.30 mg hydrate(Or equivalent amount of Dapagliflozin) Microcrystalline Cellulose 50-90mg 60-115 mg 60-115 mg 120-230 mg Lactose 10-30 mg 12.5-38 mg 12.5-38 mg25-75 mg Crospovidone 2-10 mg 2.5-13 mg 2.5-13 mg 5-25 mg SiliconDioxide 0.5-4 mg 0.6-5 mg 0.6-5 mg 1-10 mg Magnesium Stearate 0.5-2.0 mg0.6-2.5 mg 0.6-2.5 mg 1-5 mg Antioxidant and/or chelating agent 0-0.5 mg0-0.6 mg 0-0.6 mg 0-1.25 mg

B. Stock Granulation Procedure

-   -   1. Mix dapagliflozin propylene glycol hydrate or dapagliflozin        with microcrystalline cellulose.    -   2. Pass the mixture from step 1 through a suitable mill.    -   3. Mix the blend from step 2 with microcrystalline cellulose,        lactose anhydrous, crospovidone, silicon dioxide.    -   4. Mix the blend from step 3 with magnesium stearate.    -   5. Dry granulate the powder blend from Step 4.    -   6. Size the granulation from Step 5 using appropriate sieve(s).    -   7. Determine the yield based on step 6.    -   8. Mix the granules from Step 7 with remaining amount of        crospovidone, and silicon dioxide.    -   9. Mix granules from step 8 with remaining amount of magnesium        stearate.

Tablets or capsules of various strengths (1-20 mg) can be prepared usingdifferent weights of this granulation.

Tabletting/capsule filling operations: Same as other formulationsprovided herein.

Film coating: Polyvinyl alcohol (PVA), titanium dioxide, polyethyleneglycol, talc, and colorant.

1. An immediate release pharmaceutical formulation comprisingdapagliflozin propylene glycol hydrate and a pharmaceutically acceptablecarrier, wherein the dapagliflozin propylene glycol hydrate formulationis in a form selected from the group consisting of a tablet, a stockgranulation, and a capsule, wherein the dapagliflozin propylene glycolhydrate is present in an amount to provide a daily dose within the rangeof from about 0.1 to about 750 mg per day in single or divided doses ormultiple doses, which is administered 1 to 4 times, wherein thedapagliflozin propylene glycol hydrate is present in an amount withinthe range of from 0.1% to 70% of tablet or capsule fill; and thepharmaceutically acceptable carrier comprises: one or more bulkingagents/binders in an amount within the range of from 1% to 95% by weightof tablet or capsule fill, the one or more bulking agents/binderscomprising one or more of anhydrous lactose in an amount within therange of 0% to 95% by weight of tablet or capsule fill, microcrystallinecellulose in an amount within the range of 0% to 95% by weight of tabletor capsule fill, and pregelatinized starch in an amount within the rangeof 0 to 95% by weight of tablet or capsule fill; one or moredisintegrants in an amount within the range of from 0% to 20% by weightof tablet or capsule fill, the one or more disintegrants comprising oneor more of croscarmellose sodium in an amount within the range of 0% to20% by weight of tablet or capsule fill, crospovidone in an amountwithin the range of 0% to 12% by weight of tablet or capsule fill, andsodium starch glycolate in an amount within the range of 0% to 20% byweight of tablet or capsule fill; one or more glidants and/oranti-adherents comprising one or more of talc and silicon dioxide in anamount within the range from 0% to 10% by weight of tablet or capsulefill; and one or more lubricants comprising magnesium stearate in anamount within the range of 0.1% to 5% by weight of tablet or capsulefill.
 2. The pharmaceutical formulation according to claim 1, whereinthe dapagliflozin propylene glycol hydrate is


3. The formulation as defined in claim 1 in the form of a stockgranulation for loading in capsules or forming tablets.
 4. Theformulation as defined in claim 3 comprising: a) dapagliflozin propyleneglycol hydrate, wherein the dapagliflozin propylene glycol hydrate ispresent in an amount within the range of from about 0.1% to about 30% byweight of tablet or capsule fill; b) bulking agents in a total amountwithin the range of from about 10% to about 85% by weight of tablet orcapsule fill comprising one or more of lactose present in an amountwithin the range of from about 20% to about 75% by weight of tablet orcapsule fill, and microcrystalline cellulose present in an amount withinthe range of from about 20% to about 75% by weight of tablet or capsulefill; c) a binder comprising pregelatinized starch present in an amountwithin the range of from about 10% to about 75% by weight of tablet orcapsule fill; d) disintegrants in a total amount within the range offrom about 2% to about 10% by weight of tablet or capsule fill,comprising one or more of croscarmellose sodium present in an amountwithin the range of from about 2% to about 10% by weight of tablet orcapsule fill, crospovidone present in an amount within the range of fromabout 4% to about 10% by weight of tablet or capsule fill, and sodiumstarch glycolate present in an amount within the range of from about 2%to about 10% by weight of tablet or capsule fill; e) one or moreglidants and/or anti-adherents comprising talc and/or silicon dioxide,wherein the total amount of glidant and/or anti-adherent is present inan amount within the range of from about 1% to about 10% by weight oftablet or capsule fill; f) a lubricant comprising magnesium stearatepresent in an amount within the range of from about 0.2% to about 2% byweight of tablet or capsule fill; and g) optionally further comprisingan outer protective coating layer comprising a coating polymer andoptionally comprising one or more of the following: a plasticizer(s),anti-tacking agent(s), glidant(s), and colorant(s), wherein the totalamount of the outer protective coating layer is present in an amountwithin the range of from about 1% to about 5% by weight of tablet orcapsule fill.
 5. The formulation as defined in claim 3 in the form of acapsule filled with a stock granulation comprising: a) dapagliflozinpropylene glycol hydrate, wherein the dapagliflozin propylene glycolhydrate is present in an amount of 10% by weight of capsule fill; b)microcrystalline cellulose, wherein the microcrystalline cellulose ispresent in an amount of 68.75% by weight of capsule fill; c)pregelatinized starch, wherein the pregelatinized starch is present inan amount of 15% by weight of capsule fill; d) sodium starch glycolate,wherein the sodium starch glycolate is present in an amount of 3% byweight of capsule fill; e) silicon dioxide, wherein the silicon dioxideis present in an amount of 2% by weight of capsule fill; and f)magnesium stearate, wherein the magnesium stearate is present in anamount of 1.25% by weight of capsule fill.
 6. The formulation as definedin claim 3 in the form of a capsule filled with a stock granulationcomprising: a) dapagliflozin propylene glycol hydrate, wherein thedapagliflozin propylene glycol hydrate is present in an amount of 22.8%by weight of capsule fill; b) microcrystalline cellulose, wherein themicrocrystalline cellulose is present in an amount of 55.95% by weightof capsule fill; c) pregelatinized starch, wherein the pregelatinizedstarch is present in an amount of 15% by weight of capsule fill; d)sodium starch glycolate, wherein the sodium starch glycolate is presentin an amount of 3% by weight of capsule fill; e) silicon dioxide,wherein the silicon dioxide is present in an amount of 2% by weight ofcapsule fill; and f) magnesium stearate, wherein the magnesium stearateis present in an amount of 1.25% by weight of capsule fill.
 7. Theformulation as defined in claim 3 in the form of a 2.5 mg dapagliflozindose tablet comprising: a) dapagliflozin propylene glycol hydrate,wherein the dapagliflozin propylene glycol hydrate is present in anamount of 3.08 mg; b) microcrystalline cellulose, wherein themicrocrystalline cellulose is present in an amount of 67.11 mg; c)anhydrous lactose, wherein the anhydrous lactose is present in an amountof 25 mg; d) crospovidone, wherein the crospovidone is present in anamount of 8.75 mg; e) croscarmellose sodium, wherein the croscarmellosesodium is present in an amount of 3.75 mg; f) talc, wherein the talc ispresent in an amount of 12.5 mg; g) silicon dioxide, wherein the silicondioxide is present in an amount of 2.88 mg; and h) magnesium stearate,wherein the magnesium stearate is present in an amount of 1.94 mg. 8.The formulation as defined in claim 3 in the form of a 10 mgdapagliflozin dose tablet comprising: a) dapagliflozin propylene glycolhydrate, wherein the dapagliflozin propylene glycol hydrate is presentin an amount of 12.3 mg; b) microcrystalline cellulose, wherein themicrocrystalline cellulose is present in an amount of 57.89 mg; c)anhydrous lactose, wherein the anhydrous lactose is present in an amountof 25 mg; d) crospovidone, wherein the crospovidone is present in anamount of 8.75 mg; e) croscarmellose sodium, wherein the croscarmellosesodium is present in an amount of 3.75 mg; f) talc, wherein the talc ispresent in an amount of 12.5 mg; g) silicon dioxide, wherein the silicondioxide is present in an amount of 2.88 mg; and h) magnesium stearate,wherein the magnesium stearate is present in an amount of 1.94 mg. 9.The formulation as defined in claim 3 in the form of a 50 mgdapagliflozin dose tablet comprising: a) dapagliflozin propylene glycolhydrate, wherein the dapagliflozin propylene glycol hydrate is presentin an amount of 61.66 mg; b) microcrystalline cellulose, wherein themicrocrystalline cellulose is present in an amount of 114.09 mg; c)anhydrous lactose, wherein the anhydrous lactose is present in an amountof 62.6 mg; d) crospovidone, wherein the crospovidone is present in anamount of 21.91 mg; e) croscarmellose sodium, wherein the croscarmellosesodium is present in an amount of 9.39 mg; f) talc, wherein the talc ispresent in an amount of 31.3 mg; g) silicon dioxide, wherein the silicondioxide is present in an amount of 7.2 mg; and h) magnesium stearate,wherein the magnesium stearate is present in an amount of 4.85 mg. 10.The formulation as defined in claim 1, wherein the dapagliflozinpropylene glycol hydrate is present in an amount within the range offrom about 0.1% to about 30% of the stock granulation; the one or morebulking agents are microcrystalline cellulose and anhydrous lactose,present in an amount within the range of from about 10% to about 85% byweight of the stock granulation; a separate binder is not present; thedisintegrant is crospovidone and croscarmellose sodium present in anamount within the range of from about 0.25% to about 10% by weight ofthe stock granulation; the glidant and/or anti-adherent is talc andsilicon dioxide present in an amount within the range from about 1% toabout 15% by weight of the stock granulation; and the lubricant ismagnesium stearate present in an amount within the range from about 0.2%to about 2% by weight of the stock granulation.
 11. An immediate releasepharmaceutical formulation comprising dapagliflozin propylene glycolhydrate and a pharmaceutically acceptable carrier, wherein thedapagliflozin propylene glycol hydrate formulation is in a form selectedfrom the group consisting of a tablet, a stock granulation, and acapsule, wherein the dapagliflozin propylene glycol hydrate is presentin an amount to provide a daily dose within the range of from about 0.1to about 750 mg per day in single or divided doses or multiple doses,which is administered 1 to 4 times, in the form of a stock granulationfor loading in capsules or forming tablets, the stock granulationcomprising: dapagliflozin propylene glycol hydrate is present in anamount within the range of from about 0.1% to about 30% of the stockgranulation; one or more bulking agents in an amount within the range offrom about 10% to about 85% by weight of the stock granulation;optionally one or more binders in an amount within the range of fromabout 1% to about 10% by weight of the stock granulation; optionally oneor more disintegrants in an amount within the range of from about 0.25%to about 10% by weight of the stock granulation; optionally one or moreglidants and/or anti-adherents in an amount within the range from about1% to about 15% by weight of the stock granulation; and optionally oneor more lubricants in an amount within the range from about 0.2% toabout 2% by weight of the stock granulation.
 12. The formulation asdefined in claim 1 in the form of a tablet or capsule, wherein thedapagliflozin propylene glycol hydrate is present in an amount withinthe range of from 0.1% to 30% of tablet or capsule fill; and thepharmaceutically acceptable carrier comprises: one or more bulkingagents/binders in an amount within the range of from 10 to 85% by weightof tablet or capsule fill, the one or more bulking agents/binderscomprising one or more of anhydrous lactose in an amount within therange of 20 to 75% by weight of tablet or capsule fill, microcrystallinecellulose in an amount within the range of 20 to 75% by weight of tabletor capsule fill, and pregelatinized starch in an amount within the rangeof 10 to 75% by weight of tablet or capsule fill; one or moredisintegrants in an amount within the range of from 0.25 to 10% byweight of tablet or capsule fill, the one or more disintegrantscomprising one or more of croscarmellose sodium in an amount within therange of 2 to 10% by weight of tablet or capsule fill, crospovidone inan amount within the range of 4 to 10% by weight of tablet or capsulefill, and sodium starch glycolate in an amount within the range of 2 to10% by weight of tablet or capsule fill; one or more glidants and/oranti-adherents comprising one or more of talc and silicon dioxide in anamount within the range from 1 to 4% by weight of tablet or capsulefill; and one or more lubricants comprising magnesium stearate in anamount within the range of 0.2 to 2% by weight of tablet or capsulefill.
 13. The formulation as defined in claim 12 in the form of a tabletor capsule, wherein the dapagliflozin propylene glycol hydrate ispresent in an amount within the range of from 0.1% to 30% of tablet orcapsule fill; the one or more bulking agents/binders are anhydrouslactose in an amount within the range of 20% to 75% by weight of tabletor capsule fill, and microcrystalline cellulose in an amount within therange of 20% to 75% by weight of tablet or capsule fill; the one or moredisintegrants are croscarmellose sodium in an amount within the range of2% to 10% by weight of tablet or capsule fill, and crospovidone in anamount within the range of 4% to 10% by weight of tablet or capsulefill; the one or more glidants and/or anti-adherents are talc andsilicon dioxide in an amount within the range from 1% to 10% by weightof tablet or capsule fill; and the one or more lubricants are magnesiumstearate in an amount within the range of 0.2% to 2% by weight of tabletor capsule fill.